Acute Respiratory Distress Syndrome

Complex MONDO:0006502 Pathograph 25 Show in embeddings browser acute respiratory failure lung disorder

Acute respiratory distress syndrome is an acute, diffuse inflammatory lung injury that follows a direct pulmonary or indirect systemic insult. Increased permeability of the pulmonary microvascular endothelium and alveolar epithelium produces noncardiogenic pulmonary edema and loss of aerated lung, causing bilateral opacities, shunt physiology, reduced compliance, and acute hypoxemic respiratory failure. ARDS is a clinically and biologically heterogeneous syndrome rather than a single etiology or invariant histologic lesion.

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11
Pathophys.
1
Histopath.
4
Phenotypes
2
Hypotheses
1
Gaps
25
Pathograph
8
Medical Actions
4
Subtypes
2
Models
1
Deep Research
◆

Subtypes

4
age group
Adult Acute Respiratory Distress Syndrome MONDO:0100130
ARDS in adults, classified clinically by the severity of acute hypoxemia and recognized in intubated, nonintubated, and resource-limited settings under the 2024 global definition.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"We propose a new global definition of ARDS that builds on the Berlin definition."
The international consensus document defines the current clinical scope used for adult ARDS.
Pediatric Acute Respiratory Distress Syndrome MONDO:0100131
ARDS in critically ill children, for which developmental differences in lung and immune biology and pediatric-specific diagnostic criteria warrant a distinct subtype.
Show evidence (1 reference)
PMID:35913450 SUPPORT Other
"Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies."
This pediatric-focused review establishes PARDS as a clinically important child-specific form and describes its distinct evidence base.
biological subphenotype
Hyperinflammatory ARDS subphenotype
A latent-class-analysis phenotype enriched for inflammatory biomarkers, vasopressor use, metabolic acidosis, fewer ventilator-free days, and higher mortality. This is a research subphenotype rather than part of the clinical ARDS definition or a validated bedside diagnosis.
Show evidence (2 references)
PMID:37487152 SUPPORT Other
"Last, developments in ARDS subphenotyping, specifically latent class analysis–based hyper- and hypo-inflammatory phenotypes based on plasma biomarkers and clinical data, were not integrated into the current definition (33, 72–78)."
The global consensus document recognizes these reproducible research phenotypes but explicitly excludes them from the clinical definition.
PMID:42432720 SUPPORT Other
"Clinical phenotyping studies have identified a hyperinflammatory ARDS subphenotype characterized by markedly elevated inflammatory biomarkers, greater vasopressor use, metabolic acidosis, fewer ventilator-free days, and substantially higher mortality compared with hypo inflammatory phenotypes [9]."
The narrative review describes the clinical and biomarker enrichment of the hyperinflammatory phenotype; PARTIAL preserves its secondary and investigational status.
Hypoinflammatory ARDS subphenotype
A lower-inflammatory latent-class-analysis phenotype used in retrospective research stratification. A proposed metabolically exhausted state with reduced mitochondrial reserve is emerging and should not be treated as an established mechanism or a validated bedside diagnosis.
Show evidence (2 references)
PMID:37487152 SUPPORT Other
"Although these phenotypes have been demonstrated across multiple clinical trial populations and observational cohorts (79), prospective validation with point-of-care biomarker platforms is needed to determine if these phenotypes are unique to ARDS or have broader applicability to sepsis, and how..."
The consensus document supports cross-cohort reproducibility while retaining the unresolved specificity, validation, and management gaps.
PMID:42432720 SUPPORT Other
"In contrast, hypo inflammatory phenotypes may represent states of metabolic exhaustion with reduced mitochondrial reserve capacity and impaired ability to sustain reparative responses [9, 37]."
The review proposes a metabolic interpretation of the hypoinflammatory phenotype; the hedged wording and secondary evidence warrant PARTIAL.
◈

Mechanistic Hypotheses

2
Alveolar-Capillary Permeability Injury Model
alveolar_capillary_injury_model CANONICAL
Evidence balance 1 support
A direct pulmonary or indirect systemic insult initiates dysregulated innate inflammation and coagulation. Macrophage activation and recruited neutrophils injure the alveolar epithelium and pulmonary endothelium, increasing barrier permeability. Protein-rich edema, loss of aerated lung, and atelectasis then produce shunt physiology, reduced compliance, and hypoxemic respiratory failure.
Pathograph links
Direct Pulmonary or Indirect Systemic Insult -> Alveolar Macrophage and Cytokine Activation INDIRECT KNOWN INTERMEDIATES Pathogen-associated or damage-associated signals engage innate sensing in resident and recruited immune cells.
Alveolar Macrophage and Cytokine Activation -> Neutrophil Oxidative and Proteolytic Injury INDIRECT KNOWN INTERMEDIATES Cytokines and chemoattractants recruit and activate neutrophils in the alveolar compartment.
Neutrophil Oxidative and Proteolytic Injury -> Alveolar-Capillary Barrier Disruption INDIRECT KNOWN INTERMEDIATES Oxidants, proteases, and inflammatory mediators injure epithelial and endothelial barrier cells.
Ventilator-Induced Lung Injury -> Alveolar-Capillary Barrier Disruption INDIRECT KNOWN INTERMEDIATES Excessive mechanical stress adds epithelial and endothelial injury to the pre-existing inflammatory permeability lesion.
Alveolar-Capillary Barrier Disruption -> Protein-Rich Alveolar Edema and Loss of Aerated Lung DIRECT Increased barrier permeability permits fluid and protein to flood interstitial and alveolar compartments.
Alveolar-Capillary Barrier Disruption -> Intra-Alveolar Coagulation and Fibrin Deposition INDIRECT KNOWN INTERMEDIATES Injured alveolar epithelium sheds anticoagulant molecules and releases tissue factor, shifting the alveolar compartment toward coagulation.
Intra-Alveolar Coagulation and Fibrin Deposition -> Fibroproliferative Remodeling and Fibrosis INDIRECT KNOWN INTERMEDIATES In nonresolving injury, fibrin-rich alveolar organization provides a provisional matrix and procoagulant milieu that can feed remodeling.
Protein-Rich Alveolar Edema and Loss of Aerated Lung -> Shunt Physiology and Hypoxemic Respiratory Failure DIRECT Perfusion of fluid-filled or collapsed alveoli creates shunt and severe gas-exchange failure.
Protein-Rich Alveolar Edema and Loss of Aerated Lung -> Resolution and Alveolar Repair INDIRECT KNOWN INTERMEDIATES When the inciting injury and inflammation are controlled, macrophage programs, alveolar epithelial proliferation, ion transport, and barrier repair can clear edema and restore gas exchange.
Protein-Rich Alveolar Edema and Loss of Aerated Lung -> Fibroproliferative Remodeling and Fibrosis INDIRECT KNOWN INTERMEDIATES In a subset with persistent injury or dysregulated repair, the injured alveolar compartment progresses toward fibroproliferative remodeling and structural fibrosis rather than resolution.
Protein-Rich Alveolar Edema and Loss of Aerated Lung -> Noncardiogenic pulmonary edema DIRECT Protein-rich permeability edema is the tissue mechanism represented by the clinical pulmonary-edema phenotype.
Protein-Rich Alveolar Edema and Loss of Aerated Lung -> Bilateral pulmonary opacities INDIRECT KNOWN INTERMEDIATES Bilateral edema, collapse, and loss of aeration produce the characteristic bilateral radiographic or ultrasound abnormalities.
Shunt Physiology and Hypoxemic Respiratory Failure -> Hypoxemia DIRECT Intrapulmonary shunt and impaired gas exchange directly lower arterial oxygenation.
Shunt Physiology and Hypoxemic Respiratory Failure -> Acute hypoxemic respiratory failure DIRECT Severe shunt physiology culminates in acute hypoxemic respiratory failure.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"ARDS is an acute, diffuse, inflammatory lung injury precipitated by a risk factor such as pneumonia, nonpulmonary infection, trauma, transfusion, burn, aspiration, or shock. The resulting injury leads to pulmonary edema from an increase in pulmonary vascular and alveolar epithelial permeability."
The global consensus definition states the canonical insult-to-barrier-leak framework used by the main causal graph.
Immunometabolic Persistence and Metabolic Resilience Model
immunometabolic_resilience_model EMERGING
Evidence balance 1 support
Sustained glycolytic programming, impaired mitochondrial oxidative phosphorylation, redox imbalance, and bioactive metabolite signaling in immune and structural lung cells may amplify inflammation and delay alveolar-capillary repair. The related concept of metabolic resilience proposes that recovery depends partly on restoring coordinated mitochondrial function, substrate use, and redox balance. These mechanisms may help explain clinical heterogeneity, but they are not yet validated as a diagnostic endotype or treatment-selection framework.
Much of the pathway-level causality and therapeutic rationale is derived from experimental systems, sepsis extrapolation, or associative human multi-omics. No metabolism-targeted ARDS therapy or bedside metabolic-resilience assay has established prospective clinical utility.
Pathograph links
Immunometabolic Reprogramming and Mitochondrial Dysfunction -> Alveolar-Capillary Barrier Disruption INDIRECT UNKNOWN INTERMEDIATES Bioenergetic failure and metabolite signaling may amplify inflammatory injury and limit ATP-dependent epithelial and endothelial repair.
Show evidence (1 reference)
PMID:42432720 SUPPORT Other
"Emerging evidence suggests that immunometabolic reprogramming, characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and altered metabolite signalling, plays a critical role in shaping immune-cell activation, inflammatory persistence, and tissue repair during..."
The issue's narrative review directly advances the immunometabolic model, while its wording and study design justify EMERGING rather than CANONICAL status.
?

Discussions and Knowledge Gaps

1
Do longitudinal immunometabolic states causally define reproducible ARDS endotypes that predict recovery and treatment response, and can metabolic resilience be measured prospectively well enough to guide therapy?
KNOWLEDGE GAP OPEN disc_ards_metabolic_endotype_validation
Attached to
pathophysiology#Immunometabolic Reprogramming and Mitochondrial Dysfunction
PMID:42432720 synthesizes glycolytic shifts, impaired oxidative phosphorylation, metabolite signaling, and mitochondrial dysfunction into a metabolic-resilience framework. However, it is a narrative review, human multi-omic studies are largely associative and compartment-dependent, and some longitudinal claims are extrapolated from sepsis or experimental acute lung injury. Prospective ARDS-specific validation is needed to establish whether these metabolic states are causal, stable enough for bedside classification, and predictive of benefit from a metabolism-targeted intervention rather than merely markers of severity.
Show evidence (1 reference)
PMID:42432720 SUPPORT Other
"Multi-omic studies further demonstrate that distinct metabolic signatures are associated with ARDS phenotypes, disease severity, and treatment responsiveness."
The association of metabolic signatures with phenotype and response is the evidence base that motivates, but does not resolve, the prospective causal and treatment-selection question.
⚙

Pathophysiology

11
Direct Pulmonary or Indirect Systemic Insult
Pneumonia, aspiration, inhalational injury, or lung contusion can directly injure the lung, whereas sepsis, pancreatitis, major trauma, shock, burns, and transfusion can initiate systemic inflammation and endothelial injury. These heterogeneous triggers converge on acute diffuse lung injury.
Alveolar-Capillary Permeability Injury Model
Alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Human airway-on-a-chip chlorine gas exposure model ORGAN ON CHIP Delivers a graded, precisely metered inhalational chemical insult to human airway tissue, with a dose-response spanning recoverable injury at 10 ppm through irreversible barrier loss at 30 ppm.
Downstream
Alveolar Macrophage and Cytokine Activation Pathogen-associated or damage-associated signals engage innate sensing in resident and recruited immune cells. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"ARDS can be precipitated by intrapulmonary factors or extrapulmonary factors, which can lead to severe hypoxemia."
The broad mechanistic review supports both pulmonary and extrapulmonary initiating classes without making any one etiology necessary.
Alveolar Macrophage and Cytokine Activation
Alveolar macrophages recognize pathogen- or damage-associated molecular patterns and adopt a proinflammatory program. Cytokines and chemokines, including TNF, IL-1 beta, and CXCL8/IL-8, amplify local inflammation and recruit circulating neutrophils.
Alveolar-Capillary Permeability Injury Model
Alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology.
TNF hgnc:11892 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves TNF (hgnc:11892). hgnc:11892 is a gene from the HUGO Gene Nomenclature Committee. IL1B hgnc:5992 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves IL1B (hgnc:5992). hgnc:5992 is a gene from the HUGO Gene Nomenclature Committee.
Inflammatory response GO:0006954 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Inflammatory response (GO:0006954). GO:0006954 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Neutrophil Oxidative and Proteolytic Injury Cytokines and chemoattractants recruit and activate neutrophils in the alveolar compartment. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"Macrophage PRRs bind to disease-related or pathogen-related molecules, activating macrophages into proinflammatory phenotypes and thereby triggering the release of proinflammatory cytokines and neutrophil chemoattractants such as interleukin (IL)-8, tumor necrosis factor alfa (TNFalpha), and IL-1beta."
The review directly links macrophage pattern recognition to inflammatory mediator release and neutrophil recruitment.
Neutrophil Oxidative and Proteolytic Injury
Recruited neutrophils traverse the pulmonary microvascular and epithelial barriers and release reactive oxygen species, proteases, lipid mediators, and extracellular traps. These antimicrobial responses become injurious when diffuse or persistent and contribute to epithelial and endothelial damage.
Alveolar-Capillary Permeability Injury Model
Neutrophil CL:0000775 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Neutrophil (CL:0000775). CL:0000775 is a cell type from the Cell Ontology.
Neutrophil chemotaxis GO:0030593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Neutrophil chemotaxis (GO:0030593). GO:0030593 is a biological process from the Gene Ontology. ↑ INCREASED Reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Alveolar-Capillary Barrier Disruption Oxidants, proteases, and inflammatory mediators injure epithelial and endothelial barrier cells. Alveolar-Capillary Permeability Injury Model
Show evidence (2 references)
PMID:39866839 SUPPORT Other
"During this process, multiple harmful mediators, including reactive oxygen species (ROS), proteases, and proinflammatory lipid mediators such as prostaglandins and leukotrienes, are released simultaneously."
The review describes neutrophil transit and the damaging mediator classes that connect recruitment to barrier injury.
PMID:37283946 SUPPORT Human Clinical
"In particular, a significant enhancement of the oxidative stress response was observed in the neutrophil subpopulation."
Patient peripheral-blood single-cell and bulk transcriptomics provide human evidence for enhanced neutrophil oxidative-stress programs, while the small, etiology-specific sample limits generalization.
Immunometabolic Reprogramming and Mitochondrial Dysfunction
Immune and structural lung cells can shift toward glycolysis while mitochondrial oxidative phosphorylation and redox control deteriorate. Lactate, succinate, extracellular ATP, and mitochondrial danger signals may then act as signaling mediators that sustain inflammatory activation and impair energetically demanding barrier repair. This is modeled as an emerging modifier rather than a required step in every patient.
Immunometabolic Persistence and Metabolic Resilience Model
Alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology. Pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology. Pulmonary capillary endothelial cell CL:4028001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary capillary endothelial cell (CL:4028001). CL:4028001 is a cell type from the Cell Ontology.
NLRP3 hgnc:16400 HUGO Gene Nomenclature Committee (hgnc) Relation: this pathophysiological event involves this gene This pathophysiological event involves NLRP3 (hgnc:16400). hgnc:16400 is a gene from the HUGO Gene Nomenclature Committee.
Glycolytic process GO:0006096 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Glycolytic process (GO:0006096). GO:0006096 is a biological process from the Gene Ontology. ↑ INCREASED Oxidative phosphorylation GO:0006119 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Oxidative phosphorylation (GO:0006119). GO:0006119 is a biological process from the Gene Ontology. ↓ DECREASED Reactive oxygen species metabolic process GO:0072593 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Reactive oxygen species metabolic process (GO:0072593). GO:0072593 is a biological process from the Gene Ontology. ↑ INCREASED
Downstream
Alveolar-Capillary Barrier Disruption Bioenergetic failure and metabolite signaling may amplify inflammatory injury and limit ATP-dependent epithelial and endothelial repair. Immunometabolic Persistence and Metabolic Resilience Model
Show evidence (2 references)
PMID:42432720 SUPPORT Other
"During acute lung injury, immune and structural lung cells undergo metabolic shifts characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and accumulation of bioactive metabolites such as lactate, succinate, and extracellular adenosine triphosphate (ATP)."
The review supports the specific metabolic changes represented in this emerging modifier node.
PMID:42432720 SUPPORT Other
"Beyond reflecting metabolic stress, these metabolites function as signalling mediators that are associated with amplified inflammatory pathways, compromised alveolar-capillary barrier integrity, and sustained lung injury."
The evidence is marked PARTIAL because the review describes association and mechanistic plausibility rather than proving this causal edge in an unselected human ARDS population.
Ventilator-Induced Lung Injury
Positive-pressure ventilation can amplify established ARDS through overdistension, cyclic opening and closing, and patient-ventilator dyssynchrony. Lung-protective tidal volumes and, in selected early severe disease, neuromuscular blockade limit this iatrogenic stretch-injury loop.
Alveolar-Capillary Permeability Injury Model
Alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Organoid-derived Pseudomonas pneumonia-on-a-chip (VAP) model ORGAN ON CHIP Raising cyclic strain from physiological to hyperphysiological levels increased apparent permeability and, under infection, increased bacterial counts in the vascular channel. This reproduces the clinical interaction in which ventilation-associated overdistension worsens an infectious insult rather than merely coexisting with it.
Downstream
Alveolar-Capillary Barrier Disruption Excessive mechanical stress adds epithelial and endothelial injury to the pre-existing inflammatory permeability lesion. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"NMBAs are a commonly used adjunctive therapy for patients with ARDS (16, 56). The mechanism of benefit is unclear, but likely involves decreasing ventilator-induced lung injury via a reduction in patient–ventilator dyssynchrony in addition to reducing oxygen consumption, inflammation, and..."
The guideline explicitly recognizes ventilator-induced injury as an ARDS amplification mechanism and identifies dyssynchrony as one contributor.
Alveolar-Capillary Barrier Disruption
Injury to pulmonary capillary endothelial cells and pulmonary alveolar type 1 and type 2 cells disrupts intercellular junctions, ion transport, and barrier selectivity. The resulting rise in vascular and epithelial permeability allows protein-rich fluid and inflammatory cells to enter the interstitium and alveolar space.
Alveolar-Capillary Permeability Injury Model
Pulmonary alveolar type 1 cell CL:0002062 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary alveolar type 1 cell (CL:0002062). CL:0002062 is a cell type from the Cell Ontology. Pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology. Pulmonary capillary endothelial cell CL:4028001 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary capillary endothelial cell (CL:4028001). CL:4028001 is a cell type from the Cell Ontology.
Positive regulation of vascular permeability GO:0043117 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Positive regulation of vascular permeability (GO:0043117). GO:0043117 is a biological process from the Gene Ontology. ↑ INCREASED
Alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Experimental models
Human airway-on-a-chip chlorine gas exposure model ORGAN ON CHIP Epithelial junctional gaps appeared immediately after exposure, and endothelial junctional disruption followed only at 72 hours despite the endothelium never being directly exposed. The delay is the point: it establishes that barrier injury propagates from the epithelial to the endothelial layer rather than both being independently damaged.
Organoid-derived Pseudomonas pneumonia-on-a-chip (VAP) model ORGAN ON CHIP Infection combined with hyperphysiological strain disrupted the alveolar-capillary barrier and allowed bacteria to cross into the vascular compartment, reproducing the permeability lesion together with its functional consequence.
Downstream
Protein-Rich Alveolar Edema and Loss of Aerated Lung Increased barrier permeability permits fluid and protein to flood interstitial and alveolar compartments. Alveolar-Capillary Permeability Injury Model
Intra-Alveolar Coagulation and Fibrin Deposition Injured alveolar epithelium sheds anticoagulant molecules and releases tissue factor, shifting the alveolar compartment toward coagulation. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"Inflammatory dysregulation, inappropriate accumulation and activity of white blood cells and platelets, uncontrolled activation of coagulation pathways, and changes in the permeability of alveolar endothelial and epithelial barriers are the core pathological and physiological changes in acute..."
The review identifies inflammatory, coagulation, endothelial, and epithelial barrier changes as core ARDS pathology.
Intra-Alveolar Coagulation and Fibrin Deposition
Loss of epithelial anticoagulant activity and local tissue-factor release promote procoagulant signaling and fibrin deposition within alveoli and near injured endothelium. Persistent fibrin-rich injury can contribute to disordered organization and fibroproliferative remodeling.
Alveolar-Capillary Permeability Injury Model
Blood coagulation, fibrin clot formation GO:0072378 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves increased Blood coagulation, fibrin clot formation (GO:0072378). GO:0072378 is a biological process from the Gene Ontology. ↑ INCREASED
Alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Fibroproliferative Remodeling and Fibrosis In nonresolving injury, fibrin-rich alveolar organization provides a provisional matrix and procoagulant milieu that can feed remodeling. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"driving the release of procoagulant factors and fibrin deposition in the alveoli as well as near endothelial cells."
The review directly supports local procoagulant-factor release and fibrin deposition in injured alveolar and endothelial compartments.
Protein-Rich Alveolar Edema and Loss of Aerated Lung
Increased permeability produces noncardiogenic interstitial and alveolar edema. Fluid-filled and gravity-dependent collapsed alveoli reduce the ventilated gas-exchange surface and contribute to low compliance without requiring elevated left-sided filling pressure.
Alveolar-Capillary Permeability Injury Model
Alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Downstream
Shunt Physiology and Hypoxemic Respiratory Failure Perfusion of fluid-filled or collapsed alveoli creates shunt and severe gas-exchange failure. Alveolar-Capillary Permeability Injury Model
Resolution and Alveolar Repair When the inciting injury and inflammation are controlled, macrophage programs, alveolar epithelial proliferation, ion transport, and barrier repair can clear edema and restore gas exchange. Alveolar-Capillary Permeability Injury Model
Fibroproliferative Remodeling and Fibrosis In a subset with persistent injury or dysregulated repair, the injured alveolar compartment progresses toward fibroproliferative remodeling and structural fibrosis rather than resolution. Alveolar-Capillary Permeability Injury Model
Noncardiogenic pulmonary edema Protein-rich permeability edema is the tissue mechanism represented by the clinical pulmonary-edema phenotype. Alveolar-Capillary Permeability Injury Model
Bilateral pulmonary opacities Bilateral edema, collapse, and loss of aeration produce the characteristic bilateral radiographic or ultrasound abnormalities. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"The resulting injury leads to pulmonary edema from an increase in pulmonary vascular and alveolar epithelial permeability. In addition, gravity-dependent atelectasis contributes to a loss of aerated lung tissue."
The global conceptual model links permeability edema and atelectasis to loss of aerated lung.
Shunt Physiology and Hypoxemic Respiratory Failure
Ventilation-perfusion mismatch and intrapulmonary shunt cause refractory arterial hypoxemia. Increased dead space and reduced respiratory-system compliance increase ventilatory demand and can culminate in acute respiratory failure requiring assisted ventilation.
Alveolar-Capillary Permeability Injury Model
Respiratory gaseous exchange by respiratory system GO:0007585 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased Respiratory gaseous exchange by respiratory system (GO:0007585). GO:0007585 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Hypoxemia Intrapulmonary shunt and impaired gas exchange directly lower arterial oxygenation. Alveolar-Capillary Permeability Injury Model
Acute hypoxemic respiratory failure Severe shunt physiology culminates in acute hypoxemic respiratory failure. Alveolar-Capillary Permeability Injury Model
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"The clinical hallmarks of ARDS are arterial hypoxemia and bilateral radiographic opacities associated with increased shunting, increased alveolar dead space, and decreased lung compliance."
The consensus definition directly supports the terminal physiology and its clinical manifestations.
Resolution and Alveolar Repair
After control of the acute injury, pulmonary alveolar type 2 cell proliferation, macrophage-mediated inflammation resolution, restoration of ion transport, and epithelial-endothelial repair can clear edema and restore gas exchange.
Pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology. Alveolar macrophage CL:0000583 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Alveolar macrophage (CL:0000583). CL:0000583 is a cell type from the Cell Ontology.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"Following early damage to the alveolar epithelium, ATII cells rapidly proliferate"
The review supports type 2 alveolar cell proliferation during the transition from injury into repair.
Fibroproliferative Remodeling and Fibrosis
When injury and repair remain dysregulated, fibroproliferative remodeling, traction bronchiectasis, volume loss, and fibrotic structural change can produce persistent respiratory impairment. This is a nonresolving fate in a subset, not an inevitable stage of ARDS.
Lung UBERON:0002048 Uberon multi-species anatomy ontology (UBERON) Relation: this pathophysiological event occurs in this anatomical location This pathophysiological event occurs in Lung (UBERON:0002048). UBERON:0002048 is an anatomical location from the Uberon multi-species anatomy ontology.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"By the time fibrosis occurs, in addition to traction bronchiectasis, large grid-like and small cystic changes may be observed in the lungs."
The review supports a distinct fibrotic structural fate while the entry preserves that it occurs only in a subset with nonresolving injury.
✶

Histopathology

1
Diffuse Alveolar Damage with Hyaline Membrane Formation
ARDS histology can show intraalveolar edema, inflammation, hyaline membrane formation, and alveolar hemorrhage in a diffuse-alveolar-damage pattern. These findings are variable and are neither universal nor required for the clinical diagnosis.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"Histological findings vary and often include intraalveolar edema, inflammation, hyaline membrane formation, and alveolar hemorrhage, often termed diffuse alveolar damage; however, these histological features are not always present and are not necessary for a clinical diagnosis of ARDS (26)."
The consensus document supports the characteristic diffuse-alveolar-damage pattern and directly supplies the non-universality and diagnostic caveat.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for Acute Respiratory Distress Syndrome Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

4
Metabolism 1
Noncardiogenic pulmonary edema HP:0100598 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary edema (HP:0100598). HP:0100598 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"The resulting injury leads to pulmonary edema from an increase in pulmonary vascular and alveolar epithelial permeability."
The consensus model directly links permeability injury to pulmonary edema.
Respiratory 3
Hypoxemia HP:0012418 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Hypoxemia (HP:0012418). HP:0012418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"The clinical hallmarks of ARDS are arterial hypoxemia and bilateral radiographic opacities associated with increased shunting, increased alveolar dead space, and decreased lung compliance."
The consensus definition names arterial hypoxemia as a clinical hallmark.
Acute hypoxemic respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:42432720 SUPPORT Other
"ARDS is characterized by diffuse alveolar damage, increased alveolar-capillary permeability, and severe hypoxemic respiratory failure."
The review directly identifies severe hypoxemic respiratory failure.
Bilateral pulmonary opacities Pulmonary opacity HP:0031457 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Pulmonary opacity (HP:0031457). HP:0031457 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:37487152 SUPPORT Other
"The committee agreed that chest imaging criteria should include bilateral radiologic (chest radiography or computed tomography) or ultrasound findings suggestive of loss of lung aeration that are not fully explained by effusions, atelectasis, or nodules/masses."
The global definition specifies bilateral imaging abnormalities and the principal exclusions.
💊

Medical Actions

8
Etiology-Directed and Intensive Supportive Care
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Identify and treat the precipitating cause while providing oxygenation, hemodynamic support, infection management when indicated, prevention of secondary injury, and organ support. ARDS has no single etiology-specific pharmacologic cure, so supportive strategies are selected by severity and patient context.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"Given the complexity of the underlying disease, treatment needs to be tailored to the problem."
The review supports etiology- and context-specific management of this heterogeneous syndrome.
Lung-Protective Low-Tidal-Volume Mechanical Ventilation
Action: mechanical ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mechanical ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. Ontology label: Mechanical Ventilation NCIT:C70909
For invasively ventilated ARDS, use low tidal volumes based on predicted body weight and limit plateau pressure to reduce ventilator-induced stretch injury. The pivotal trial compared an initial 6 mL/kg predicted body weight and plateau pressure at or below 30 cm H2O with traditional larger volumes.
Mechanism Target:
INHIBITS Ventilator-Induced Lung Injury — Lower tidal volume and plateau-pressure limitation reduce injurious mechanical stretch during invasive ventilation.
Show evidence (1 reference)
PMID:10793162 SUPPORT Human Clinical
"Traditional approaches to mechanical ventilation use tidal volumes of 10 to 15 ml per kilogram of body weight and may cause stretch-induced lung injury in patients with acute lung injury and the acute respiratory distress syndrome."
The trial directly motivates lower-volume ventilation as prevention of stretch-induced lung injury.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:10793162 SUPPORT Human Clinical
"In patients with acute lung injury and the acute respiratory distress syndrome, mechanical ventilation with a lower tidal volume than is traditionally used results in decreased mortality and increases the number of days without ventilator use."
The multicenter randomized trial directly supports lung-protective lower-tidal-volume ventilation.
Prolonged Prone Positioning for Severe ARDS
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Use early, prolonged prone sessions in appropriately selected patients with severe ARDS alongside lung-protective ventilation; the pivotal protocol used sessions of at least 16 hours.
Mechanism Target:
MODULATES Shunt Physiology and Hypoxemic Respiratory Failure — Proning redistributes ventilation and perfusion and recruits dependent lung, thereby improving oxygenation across the shunt-dominated physiology.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"The prone position is a readily implementable intervention associated with improved oxygenation due to an increased ventilator–blood flow ratio, more uniform ventilation distribution, increased lung volume, and improved perfusion redistribution during partial alveolar re-expansion in the..."
The review directly links prone positioning to redistribution of ventilation and perfusion and improved oxygenation.
Target Phenotypes: Hypoxemia HP:0012418 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypoxemia (HP:0012418). HP:0012418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23688302 SUPPORT Human Clinical
"In patients with severe ARDS, early application of prolonged prone-positioning sessions significantly decreased 28-day and 90-day mortality."
The randomized PROSEVA trial directly supports early prolonged proning in its severe-ARDS population.
Conservative Fluid Management After Hemodynamic Stabilization
Action: fluid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is fluid therapy (NCIT:C116537). NCIT:C116537 is a clinical intervention from the NCI Thesaurus. Ontology label: Fluid Therapy NCIT:C116537
Once shock and tissue hypoperfusion are addressed, a conservative fluid strategy can reduce hydrostatic contribution to lung edema and shorten ventilatory and ICU support. The pivotal trial improved lung function and ventilator-free days but did not significantly reduce 60-day mortality.
Mechanism Target:
INHIBITS Protein-Rich Alveolar Edema and Loss of Aerated Lung — After hemodynamic stabilization, conservative fluid management limits the fluid burden superimposed on permeability edema and improves lung function.
Show evidence (1 reference)
PMID:16714767 SUPPORT Human Clinical
"Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures."
FACTT directly demonstrates improved lung function from the conservative strategy while retaining its neutral mortality result.
Target Phenotypes: Pulmonary edema HP:0100598 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Pulmonary edema (HP:0100598). HP:0100598 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:16714767 SUPPORT Human Clinical
"Although there was no significant difference in the primary outcome of 60-day mortality, the conservative strategy of fluid management improved lung function and shortened the duration of mechanical ventilation and intensive care without increasing nonpulmonary-organ failures."
The randomized FACTT trial supports conservative management for pulmonary and support-duration outcomes while preserving its neutral mortality result.
Systemic Corticosteroids
Action: systemic corticosteroid therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is systemic corticosteroid therapy (NCIT:C122080). NCIT:C122080 is a clinical intervention from the NCI Thesaurus. Ontology label: Systemic Corticosteroid Therapy NCIT:C122080
Agent: corticosteroid CHEBI:50858 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses corticosteroid (CHEBI:50858). CHEBI:50858 is a therapeutic agent from Chemical Entities of Biological Interest.
Systemic corticosteroids may be considered for ARDS, individualized to etiology, timing, infection risk, and adverse-effect profile. The current ATS recommendation is conditional and does not establish one molecule, dose, or duration for every patient.
Mechanism Target:
INHIBITS Alveolar Macrophage and Cytokine Activation — Corticosteroids suppress synthesis of proinflammatory mediators that sustain the macrophage-cytokine activation node.
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"Corticosteroids are anti-inflammatory medications that inhibit the synthesis of proinflammatory mediators present in ARDS."
The guideline directly states the anti-inflammatory mechanism used to join corticosteroid treatment to cytokine activation.
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"We suggest the use of: 1) corticosteroids for patients with ARDS (conditional recommendation, moderate certainty of evidence)"
The official guideline supports corticosteroids while the entry preserves the recommendation's conditional strength.
Higher PEEP Without Prolonged Recruitment Maneuvers
Action: mechanical ventilationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is mechanical ventilation (NCIT:C70909). NCIT:C70909 is a clinical intervention from the NCI Thesaurus. Ontology label: Mechanical Ventilation NCIT:C70909
In moderate-to-severe ARDS, higher positive end-expiratory pressure may be used to maintain recruitment as part of lung-protective ventilation, but prolonged lung recruitment maneuvers should be avoided.
Target Phenotypes: Hypoxemia HP:0012418 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Hypoxemia (HP:0012418). HP:0012418 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"We suggest using higher PEEP without lung recruitment maneuvers (LRMs) as opposed to lower PEEP in patients with moderate to severe ARDS (conditional recommendation, low to moderate certainty)."
The guideline supports higher PEEP without recruitment maneuvers and states the low-to-moderate certainty explicitly.
Neuromuscular Blockade for Early Severe ARDS
Action: neuromuscular blockadeNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is neuromuscular blockade (NCIT:C158070). NCIT:C158070 is a clinical intervention from the NCI Thesaurus. Ontology label: Neuromuscular Blockade NCIT:C158070
Agent: cisatracurium CHEBI:140621 Chemical Entities of Biological Interest (CHEBI) Relation: this treatment uses this therapeutic agent This treatment uses cisatracurium (CHEBI:140621). CHEBI:140621 is a therapeutic agent from Chemical Entities of Biological Interest.
Neuromuscular blockade may be considered early in selected patients with severe ARDS when deep sedation and ventilator synchrony are required. It is not routine treatment for all ARDS because the guideline recommendation is conditional and based on low-certainty evidence.
Mechanism Target:
INHIBITS Ventilator-Induced Lung Injury — In selected early severe ARDS, blockade can reduce patient-ventilator dyssynchrony and thereby limit ventilator-induced injury.
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"NMBAs are a commonly used adjunctive therapy for patients with ARDS (16, 56). The mechanism of benefit is unclear, but likely involves decreasing ventilator-induced lung injury via a reduction in patient–ventilator dyssynchrony in addition to reducing oxygen consumption, inflammation, and..."
The guideline explicitly links neuromuscular blockade to reduced dyssynchrony and likely reduction of ventilator-induced injury.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:38032683 SUPPORT Other
"We suggest using neuromuscular blockade in patients with early severe ARDS (conditional recommendation, low certainty)"
The official guideline limits neuromuscular blockade to early severe ARDS and explicitly grades the recommendation as conditional and low certainty.
PMID:38032683 SUPPORT Other
"Although this guideline does not recommend a specific NMBA, cisatracurium was used in the two largest RCTs (60, 64) and may be associated with pleiotropic effects, including a decrease in inflammatory cytokines (68, 69), suggesting that it may be a preferable NMBA for patients with ARDS."
The guideline supports cisatracurium as the best-studied representative agent while explicitly retaining that no specific NMBA is mandated.
Venovenous Extracorporeal Membrane Oxygenation
Action: extracorporeal membrane oxygenationNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is extracorporeal membrane oxygenation (NCIT:C171507). NCIT:C171507 is a clinical intervention from the NCI Thesaurus. Ontology label: Extracorporeal Membrane Oxygenation NCIT:C171507
VV-ECMO is rescue organ support for carefully selected patients with severe, refractory ARDS after optimization of conventional lung-protective care. Patient selection, center expertise, reversibility, duration of ventilation, and complication risk are essential because certainty of benefit remains low.
Mechanism Target:
MODULATES Shunt Physiology and Hypoxemic Respiratory Failure — VV-ECMO provides extracorporeal gas exchange while the injured lung is supported, improving blood oxygen exchange in refractory respiratory failure without claiming to repair the upstream alveolar lesion.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"ECMO directly provides conditional support for patients, improves the blood oxygen exchange rate, and has an important impact on the adjustment of body hemodynamics."
The review directly links ECMO support to improved blood oxygen exchange, supporting a conservative MODULATES edge to terminal shunt physiology.
Target Phenotypes: Respiratory failure HP:0002878 Human Phenotype Ontology (HP) Relation: this treatment targets this phenotype This treatment targets Respiratory failure (HP:0002878). HP:0002878 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:38032683 SUPPORT Other
"We suggest using venovenous extracorporeal membrane oxygenation (VV-ECMO) in selected patients with severe ARDS (conditional recommendation, low certainty of evidence)."
The official guideline supports VV-ECMO only for selected severe cases and explicitly grades the evidence as low certainty.
🔬

Biochemical Markers

2
Alveolar and circulating lactate (INCREASED)
Context: Elevated lactate is an investigational, compartment-dependent marker and signaling mediator of glycolytic dominance and critical-illness stress; it is neither specific nor sufficient for ARDS diagnosis.
Show evidence (1 reference)
PMID:42432720 SUPPORT Other
"During acute lung injury, immune and structural lung cells undergo metabolic shifts characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and accumulation of bioactive metabolites such as lactate, succinate, and extracellular adenosine triphosphate (ATP)."
The review supports lactate accumulation but not its use as an ARDS-specific diagnostic biomarker, hence PARTIAL support.
Alveolar succinate (INCREASED)
Context: Succinate accumulation is an investigational local immunometabolic signal associated with disrupted mitochondrial metabolism; routine clinical measurement and ARDS-specific thresholds are not established.
Show evidence (1 reference)
PMID:42432720 SUPPORT Other
"During acute lung injury, immune and structural lung cells undergo metabolic shifts characterized by increased glycolysis, impaired mitochondrial oxidative phosphorylation, and accumulation of bioactive metabolites such as lactate, succinate, and extracellular adenosine triphosphate (ATP)."
The review supports succinate accumulation, while the entry explicitly preserves the lack of validated clinical measurement thresholds.
🔬

Diagnosis

1
Global Consensus Clinical Diagnosis
Diagnose ARDS when acute or worsening hypoxemic respiratory failure occurs within one week of a predisposing insult or new respiratory symptoms, with bilateral loss of lung aeration on radiography, CT, or qualified ultrasound, and edema not primarily explained by cardiac failure, fluid overload, collapse, effusion, or embolism. Hypoxemia can be identified by PaO2:FiO2 at or below 300 mm Hg or by SpO2:FiO2 at or below 315 when SpO2 is at or below 97%; the global definition includes specified nonintubated and resource-limited pathways.
clinical assessment NCIT:C124351 NCI Thesaurus (NCIT)
Results: Acute bilateral noncardiogenic inflammatory lung injury with qualifying hypoxemia supports the diagnosis; severity and respiratory-support category should be recorded separately.
Show evidence (2 references)
PMID:37487152 SUPPORT Other
"The committee agreed that the current time frame for the diagnosis of ARDS should be retained: acute onset or worsening of hypoxemic respiratory failure is defined as occurring within 1 week of the onset of the predisposing risk factor or within 1 week of new or worsening respiratory symptoms."
This establishes the acute diagnostic time window.
PMID:37487152 SUPPORT Other
"The committee made four main recommendations: 1) include high-flow nasal oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if oxygen saturation as measured by pulse oximetry is ⩽97%) to identify..."
The global definition supplies the oxygenation, imaging, and respiratory-support criteria represented in the diagnostic description.
📈

Progression

3
Exudative inflammatory phase
The early injury phase features proinflammatory alveolar-macrophage activation, neutrophil recruitment, epithelial injury, endothelial activation, and permeability edema. Diffuse alveolar damage may occur but is not required for the clinical diagnosis.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"During the exudative phase of ARDS, macrophages are activated by pathogens through pattern recognition receptors (PRRs), including Toll-like receptors (TLRs), leucine-rich repeat sequence receptors (NLRs), transmembrane C-type lectin receptors (CLRs), and retinoic acid-induced gene-like..."
The review defines macrophage activation as a central feature of the exudative phase.
Reparative and proliferative phase
If injury control and clearance succeed, pulmonary alveolar type 2 cells proliferate and macrophage programs shift toward inflammation resolution, epithelial regeneration, edema clearance, and structural repair.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"In the late stage of ARDS, anti-inflammatory cytokines secreted by selectively activated macrophages inhibit the inflammatory response, thereby promoting epithelial regeneration and alveolar structural remodeling."
The review describes the macrophage and epithelial transition toward repair and remodeling.
Persistent fibroproliferative or fibrotic phase
In a subset with nonresolving injury, aberrant remodeling progresses to traction bronchiectasis, reduced lung volume, and fibrotic structural change, prolonging ventilatory and functional impairment.
Show evidence (1 reference)
PMID:39866839 SUPPORT Other
"By the time fibrosis occurs, in addition to traction bronchiectasis, large grid-like and small cystic changes may be observed in the lungs."
The review describes the radiologic structural changes of the fibrotic phase; the entry limits this course to a subset rather than implying that all ARDS becomes fibrotic.
🧫

Experimental Models

2
Human airway-on-a-chip chlorine gas exposure model ORGAN_ON_CHIP namo:OrganOnChip
A microfluidic human airway chip with pseudostratified mucociliary epithelium, a biomimetic extracellular matrix hydrogel, an endothelial compartment, and integrated electrodes for transepithelial electrical resistance, coupled to a chlorine generation and delivery platform that controls concentration and exposure duration precisely. Transcriptomics and metabolomics were run across post-exposure timepoints. It addresses a gap that is unusually hard to fill any other way: human clinical data on acute chlorine exposure are scarce for obvious reasons, and animal models translate poorly.
chlorine gas 10, 20, and 30 ppm for 10 to 30 minutes medical air exposure control
Bronchial epithelial cell CL:0002328 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Bronchial epithelial cell (CL:0002328). CL:0002328 is a cell type from the Cell Ontology. Pulmonary capillary endothelial cell CL:4028001 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Pulmonary capillary endothelial cell (CL:4028001). CL:4028001 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
epithelium of bronchus UBERON:0002031 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses epithelium of bronchus (UBERON:0002031). UBERON:0002031 is an anatomical location from the Uberon multi-species anatomy ontology.
Culture
Microfluidic airway-on-a-chip at air-liquid interface with integrated TEER electrodes and controlled gas exposure
Publication
PMID:41442163
Pathograph links
Direct Pulmonary or Indirect Systemic Insult recapitulates fidelity: moderate Delivers a graded, precisely metered inhalational chemical insult to human airway tissue, with a dose-response spanning recoverable injury at 10 ppm through irreversible barrier loss at 30 ppm.
Limitations: Chlorine is one specific inhalational insult and the chip is bronchial rather than alveolar, so it models the direct pulmonary insult category only for inhaled oxidant gases and not for aspiration, pneumonia, or the indirect systemic insults that cause most ARDS.
Readouts
Transepithelial electrical resistance across chlorine dose and duration
Direction: DECREASED
Interpretation: A recoverable-to-irreversible dose-response identifies the threshold at which an inhalational insult becomes an established barrier lesion.
Show evidence (1 reference)
PMID:41442163 SUPPORT In Vitro
"Transepithelial electrical resistance (TEER) measurements of barrier function also showed recoverable function at 10 ppm Cl2, progressing to a critical loss of barrier function at higher concentrations or exposure durations."
Reports the graded barrier response to the insult this node describes.
Show evidence (1 reference)
PMID:41442163 SUPPORT In Vitro
"Epithelial barrier disruption, characterized by gap formation, was evident immediately post-Cl2 exposure and persisted through 24 h"
Supports the chip as a model of a direct pulmonary chemical insult producing sustained injury.
Alveolar-Capillary Barrier Disruption partially recapitulates fidelity: moderate Epithelial junctional gaps appeared immediately after exposure, and endothelial junctional disruption followed only at 72 hours despite the endothelium never being directly exposed. The delay is the point: it establishes that barrier injury propagates from the epithelial to the endothelial layer rather than both being independently damaged.
Limitations: The chip has no neutrophils or macrophages, so the inflammatory amplification and resolution phases that dominate barrier disruption in clinical ARDS are represented only indirectly through early epithelial-endothelial signalling. It is also airway rather than alveolar epithelium.
Readouts
Endothelial VE-cadherin junction integrity at 72 hours post-exposure
Direction: DECREASED
Interpretation: Delayed endothelial junctional loss after an exclusively epithelial exposure is evidence of trans-barrier propagation.
Show evidence (1 reference)
PMID:41442163 SUPPORT In Vitro
"In contrast, endothelial junction disruption emerged at 72 h, supporting secondary endothelial dysfunction following epithelial oxidative injury."
Directly reports the delayed, secondary endothelial injury this readout measures.
Show evidence (1 reference)
PMID:41442163 SUPPORT In Vitro
"A primary constraint is the absence of innate immune system components, limiting evaluation of inflammatory responses to early epithelial/endothelial signaling that would typically recruit neutrophils and macrophages."
The authors' own statement of the model's key limitation for a node whose clinical form is inflammation-driven; PARTIAL records informative but bounded relevance.
Organoid-derived Pseudomonas pneumonia-on-a-chip (VAP) model ORGAN_ON_CHIP namo:OrganOnChip
An alveolus chip lined with organoid-derived alveolar epithelial cells that differentiate into both type 2 and type 1-like cells, plus primary pulmonary microvascular endothelium, cycled at a respiratory-like 0.25 Hz at either physiological (5%) or hyperphysiological (10%) strain and infected with Pseudomonas aeruginosa. Comparing the two strain levels under an otherwise identical infection isolates the contribution of ventilation-associated stretch, which is the central question in ventilator-associated pneumonia and ventilator-induced lung injury.
physiological cyclic strain (5%, 0.25 Hz) hyperphysiological cyclic strain (10%, 0.25 Hz) Pseudomonas aeruginosa PAO1 infection
Pulmonary alveolar type 2 cell CL:0002063 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Pulmonary alveolar type 2 cell (CL:0002063). CL:0002063 is a cell type from the Cell Ontology. Pulmonary alveolar type 1 cell CL:0002062 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Pulmonary alveolar type 1 cell (CL:0002062). CL:0002062 is a cell type from the Cell Ontology. Pulmonary capillary endothelial cell CL:4028001 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses Pulmonary capillary endothelial cell (CL:4028001). CL:4028001 is a cell type from the Cell Ontology.
Organism
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Tissue
alveolus of lung UBERON:0002299 Uberon multi-species anatomy ontology (UBERON) Relation: this experimental model uses this anatomical location This experimental model uses alveolus of lung (UBERON:0002299). UBERON:0002299 is an anatomical location from the Uberon multi-species anatomy ontology.
Cell source
Human alveolar organoid-derived epithelial cells and primary pulmonary microvascular endothelial cells
Culture
Alveolus-on-a-chip with air-liquid interface, vascular flow, and controlled cyclic strain
Publication
PMID:41252215
Pathograph links
Ventilator-Induced Lung Injury recapitulates fidelity: moderate Raising cyclic strain from physiological to hyperphysiological levels increased apparent permeability and, under infection, increased bacterial counts in the vascular channel. This reproduces the clinical interaction in which ventilation-associated overdistension worsens an infectious insult rather than merely coexisting with it.
Limitations: Uniform cyclic strain across a chip membrane is not the regionally heterogeneous overdistension and cyclic recruitment-derecruitment of an injured ventilated lung, and the model has no immune cells, so the leukocyte-mediated component of ventilator-induced injury is absent. Readouts are at 12 hours post-infection only.
Readouts
Apparent permeability under hyperphysiological versus physiological strain
Direction: INCREASED
Interpretation: Strain-dependent permeability increase is the barrier readout for stretch injury.
Show evidence (1 reference)
PMID:41252215 SUPPORT In Vitro
"Yet, Papp was slightly increased in 10% stretched ODAECs, suggesting barrier impairment by hyperphysiological stretch."
Reports the permeability effect of strain alone; PARTIAL preserves the authors' description of the effect as slight.
Bacterial translocation to the vascular channel under increased strain
Direction: INCREASED
Interpretation: Higher vascular-channel colony counts under greater strain quantify the strain-infection interaction.
Show evidence (1 reference)
PMID:41252215 SUPPORT In Vitro
"Notably, increased cellular stretch intensified Pseudomonas infection, leading to greater barrier disruption and bacterial translocation"
Directly reports increased barrier disruption and translocation under greater strain.
Show evidence (1 reference)
PMID:41252215 SUPPORT In Vitro
"We hereby present what we believe to be the first functional Pseudomonas POC and VAP-on-a-chip model that replicates key features of disease, including enhanced mechanical strain."
Supports the chip as a model of ventilator-associated infectious lung injury, the clinical setting this node describes.
Alveolar-Capillary Barrier Disruption recapitulates fidelity: moderate Infection combined with hyperphysiological strain disrupted the alveolar-capillary barrier and allowed bacteria to cross into the vascular compartment, reproducing the permeability lesion together with its functional consequence.
Limitations: Barrier failure is measured as apparent permeability and bacterial translocation over 12 hours, without the protein-rich alveolar flooding, coagulation, or leukocyte transmigration that accompany the lesion clinically.
Readouts
Barrier disruption with bacterial translocation
Direction: INCREASED
Interpretation: Passage of bacteria from the alveolar to the vascular channel is a functional demonstration that the barrier has failed.
Show evidence (1 reference)
PMID:41252215 SUPPORT In Vitro
"Notably, increased cellular stretch intensified Pseudomonas infection, leading to greater barrier disruption and bacterial translocation"
Reports barrier disruption with translocation as a combined functional readout.
Show evidence (1 reference)
PMID:41252215 SUPPORT In Vitro
"We hereby present what we believe to be the first functional Pseudomonas POC and VAP-on-a-chip model that replicates key features of disease, including enhanced mechanical strain."
Supports the chip as informative for the alveolar-capillary barrier lesion under combined infectious and mechanical insult.
{ }

Source YAML

click to show 
name: Acute Respiratory Distress Syndrome
creation_date: "2026-08-08T19:10:07Z"
category: Complex
categories:
- Respiratory Disease
synonyms:
- ARDS
description: >-
  Acute respiratory distress syndrome is an acute, diffuse inflammatory lung
  injury that follows a direct pulmonary or indirect systemic insult. Increased
  permeability of the pulmonary microvascular endothelium and alveolar
  epithelium produces noncardiogenic pulmonary edema and loss of aerated lung,
  causing bilateral opacities, shunt physiology, reduced compliance, and acute
  hypoxemic respiratory failure. ARDS is a clinically and biologically
  heterogeneous syndrome rather than a single etiology or invariant histologic
  lesion.
parents:
- acute respiratory failure
- lung disorder
disease_term:
  preferred_term: Acute respiratory distress syndrome
  term:
    id: MONDO:0006502
    label: acute respiratory distress syndrome
has_subtypes:
- name: Adult ARDS
  display_name: Adult Acute Respiratory Distress Syndrome
  classification: age_group
  subtype_term:
    preferred_term: adult acute respiratory distress syndrome
    term:
      id: MONDO:0100130
      label: adult acute respiratory distress syndrome
  description: >-
    ARDS in adults, classified clinically by the severity of acute hypoxemia and
    recognized in intubated, nonintubated, and resource-limited settings under
    the 2024 global definition.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We propose a new global definition of ARDS that builds on the Berlin
      definition.
    explanation: >-
      The international consensus document defines the current clinical scope
      used for adult ARDS.
- name: Pediatric ARDS
  display_name: Pediatric Acute Respiratory Distress Syndrome
  classification: age_group
  subtype_term:
    preferred_term: pediatric acute respiratory distress syndrome
    term:
      id: MONDO:0100131
      label: pediatric acute respiratory distress syndrome
  description: >-
    ARDS in critically ill children, for which developmental differences in
    lung and immune biology and pediatric-specific diagnostic criteria warrant
    a distinct subtype.
  evidence:
  - reference: PMID:35913450
    reference_title: Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Pediatric acute respiratory distress syndrome (PARDS), though both common
      and deadly in critically ill children, lacks targeted therapies.
    explanation: >-
      This pediatric-focused review establishes PARDS as a clinically important
      child-specific form and describes its distinct evidence base.
- name: Hyperinflammatory ARDS subphenotype
  classification: biological_subphenotype
  description: >-
    A latent-class-analysis phenotype enriched for inflammatory biomarkers,
    vasopressor use, metabolic acidosis, fewer ventilator-free days, and higher
    mortality. This is a research subphenotype rather than part of the clinical
    ARDS definition or a validated bedside diagnosis.
  review_notes: >-
    Prospective point-of-care validation and evidence that this phenotype is
    specific to ARDS rather than critical illness or sepsis remain necessary.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Last, developments in ARDS subphenotyping, specifically latent class
      analysis–based hyper- and hypo-inflammatory phenotypes based on plasma
      biomarkers and clinical data, were not integrated into the current
      definition (33, 72–78).
    explanation: >-
      The global consensus document recognizes these reproducible research
      phenotypes but explicitly excludes them from the clinical definition.
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Clinical phenotyping studies have identified a hyperinflammatory ARDS
      subphenotype characterized by markedly elevated inflammatory biomarkers,
      greater vasopressor use, metabolic acidosis, fewer ventilator-free days,
      and substantially higher mortality compared with hypo inflammatory
      phenotypes [9].
    explanation: >-
      The narrative review describes the clinical and biomarker enrichment of
      the hyperinflammatory phenotype; PARTIAL preserves its secondary and
      investigational status.
- name: Hypoinflammatory ARDS subphenotype
  classification: biological_subphenotype
  description: >-
    A lower-inflammatory latent-class-analysis phenotype used in retrospective
    research stratification. A proposed metabolically exhausted state with
    reduced mitochondrial reserve is emerging and should not be treated as an
    established mechanism or a validated bedside diagnosis.
  review_notes: >-
    Prospective point-of-care validation and longitudinal stability of the
    phenotype are not established.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although these phenotypes have been demonstrated across multiple clinical
      trial populations and observational cohorts (79), prospective validation
      with point-of-care biomarker platforms is needed to determine if these
      phenotypes are unique to ARDS or have broader applicability to sepsis, and
      how they may affect management.
    explanation: >-
      The consensus document supports cross-cohort reproducibility while
      retaining the unresolved specificity, validation, and management gaps.
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In contrast, hypo inflammatory phenotypes may represent states of
      metabolic exhaustion with reduced mitochondrial reserve capacity and
      impaired ability to sustain reparative responses [9, 37].
    explanation: >-
      The review proposes a metabolic interpretation of the hypoinflammatory
      phenotype; the hedged wording and secondary evidence warrant PARTIAL.
mechanistic_hypotheses:
- hypothesis_group_id: alveolar_capillary_injury_model
  hypothesis_label: Alveolar-Capillary Permeability Injury Model
  status: CANONICAL
  description: >-
    A direct pulmonary or indirect systemic insult initiates dysregulated innate
    inflammation and coagulation. Macrophage activation and recruited
    neutrophils injure the alveolar epithelium and pulmonary endothelium,
    increasing barrier permeability. Protein-rich edema, loss of aerated lung,
    and atelectasis then produce shunt physiology, reduced compliance, and
    hypoxemic respiratory failure.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ARDS is an acute, diffuse, inflammatory lung injury precipitated by a risk
      factor such as pneumonia, nonpulmonary infection, trauma, transfusion,
      burn, aspiration, or shock. The resulting injury leads to pulmonary edema
      from an increase in pulmonary vascular and alveolar epithelial
      permeability.
    explanation: >-
      The global consensus definition states the canonical
      insult-to-barrier-leak framework used by the main causal graph.
- hypothesis_group_id: immunometabolic_resilience_model
  hypothesis_label: Immunometabolic Persistence and Metabolic Resilience Model
  status: EMERGING
  description: >-
    Sustained glycolytic programming, impaired mitochondrial oxidative
    phosphorylation, redox imbalance, and bioactive metabolite signaling in
    immune and structural lung cells may amplify inflammation and delay
    alveolar-capillary repair. The related concept of metabolic resilience
    proposes that recovery depends partly on restoring coordinated
    mitochondrial function, substrate use, and redox balance. These mechanisms
    may help explain clinical heterogeneity, but they are not yet validated as
    a diagnostic endotype or treatment-selection framework.
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Emerging evidence suggests that immunometabolic reprogramming,
      characterized by increased glycolysis, impaired mitochondrial oxidative
      phosphorylation, and altered metabolite signalling, plays a critical role
      in shaping immune-cell activation, inflammatory persistence, and tissue
      repair during critical illness.
    explanation: >-
      The issue's narrative review directly advances the immunometabolic model,
      while its wording and study design justify EMERGING rather than CANONICAL
      status.
  notes: >-
    Much of the pathway-level causality and therapeutic rationale is derived
    from experimental systems, sepsis extrapolation, or associative human
    multi-omics. No metabolism-targeted ARDS therapy or bedside
    metabolic-resilience assay has established prospective clinical utility.
progression:
- phase: Exudative inflammatory phase
  notes: >-
    The early injury phase features proinflammatory alveolar-macrophage
    activation, neutrophil recruitment, epithelial injury, endothelial
    activation, and permeability edema. Diffuse alveolar damage may occur but is
    not required for the clinical diagnosis.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During the exudative phase of ARDS, macrophages are activated by pathogens
      through pattern recognition receptors (PRRs), including Toll-like
      receptors (TLRs), leucine-rich repeat sequence receptors (NLRs),
      transmembrane C-type lectin receptors (CLRs), and retinoic acid-induced
      gene-like receptors (RLRs), which promote the transition of resident AM
      cells to the predominant proinflammatory phenotype.
    explanation: >-
      The review defines macrophage activation as a central feature of the
      exudative phase.
- phase: Reparative and proliferative phase
  notes: >-
    If injury control and clearance succeed, pulmonary alveolar type 2 cells
    proliferate and macrophage programs shift toward inflammation resolution,
    epithelial regeneration, edema clearance, and structural repair.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      In the late stage of ARDS, anti-inflammatory cytokines secreted by
      selectively activated macrophages inhibit the inflammatory response,
      thereby promoting epithelial regeneration and alveolar structural
      remodeling.
    explanation: >-
      The review describes the macrophage and epithelial transition toward
      repair and remodeling.
- phase: Persistent fibroproliferative or fibrotic phase
  notes: >-
    In a subset with nonresolving injury, aberrant remodeling progresses to
    traction bronchiectasis, reduced lung volume, and fibrotic structural
    change, prolonging ventilatory and functional impairment.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      By the time fibrosis occurs, in addition to traction bronchiectasis, large
      grid-like and small cystic changes may be observed in the lungs.
    explanation: >-
      The review describes the radiologic structural changes of the fibrotic
      phase; the entry limits this course to a subset rather than implying that
      all ARDS becomes fibrotic.
pathophysiology:
- name: Direct Pulmonary or Indirect Systemic Insult
  conforms_to: "alveolar_capillary_barrier_failure#Alveolar-Capillary Interface Insult"
  description: >-
    Pneumonia, aspiration, inhalational injury, or lung contusion can directly
    injure the lung, whereas sepsis, pancreatitis, major trauma, shock, burns,
    and transfusion can initiate systemic inflammation and endothelial injury.
    These heterogeneous triggers converge on acute diffuse lung injury.
  role: trigger
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Alveolar Macrophage and Cytokine Activation
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      Pathogen-associated or damage-associated signals engage innate sensing in
      resident and recruited immune cells.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Macrophage PRRs bind to disease-related or pathogen-related molecules,
        activating macrophages into proinflammatory phenotypes
      explanation: >-
        This directly supports innate pattern recognition and macrophage
        activation downstream of pathogen- or injury-related signals.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ARDS can be precipitated by intrapulmonary factors or extrapulmonary
      factors, which can lead to severe hypoxemia.
    explanation: >-
      The broad mechanistic review supports both pulmonary and extrapulmonary
      initiating classes without making any one etiology necessary.
- name: Alveolar Macrophage and Cytokine Activation
  description: >-
    Alveolar macrophages recognize pathogen- or damage-associated molecular
    patterns and adopt a proinflammatory program. Cytokines and chemokines,
    including TNF, IL-1 beta, and CXCL8/IL-8, amplify local inflammation and
    recruit circulating neutrophils.
  role: mediator
  cell_types:
  - preferred_term: Alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  genes:
  - preferred_term: TNF
    term:
      id: hgnc:11892
      label: TNF
  - preferred_term: IL1B
    term:
      id: hgnc:5992
      label: IL1B
  biological_processes:
  - preferred_term: Inflammatory response
    modifier: INCREASED
    term:
      id: GO:0006954
      label: inflammatory response
  downstream:
  - target: Neutrophil Oxidative and Proteolytic Injury
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Cytokines and chemoattractants recruit and activate neutrophils in the alveolar compartment.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Macrophage PRRs bind to disease-related or pathogen-related molecules,
        activating macrophages into proinflammatory phenotypes and thereby
        triggering the release of proinflammatory cytokines and neutrophil
        chemoattractants such as interleukin (IL)-8, tumor necrosis factor alfa
        (TNFalpha), and IL-1beta.
      explanation: >-
        The review directly links macrophage activation to cytokine and
        neutrophil-chemoattractant release.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Macrophage PRRs bind to disease-related or pathogen-related molecules,
      activating macrophages into proinflammatory phenotypes and thereby
      triggering the release of proinflammatory cytokines and neutrophil
      chemoattractants such as interleukin (IL)-8, tumor necrosis factor alfa
      (TNFalpha), and IL-1beta.
    explanation: >-
      The review directly links macrophage pattern recognition to inflammatory
      mediator release and neutrophil recruitment.
- name: Neutrophil Oxidative and Proteolytic Injury
  description: >-
    Recruited neutrophils traverse the pulmonary microvascular and epithelial
    barriers and release reactive oxygen species, proteases, lipid mediators,
    and extracellular traps. These antimicrobial responses become injurious
    when diffuse or persistent and contribute to epithelial and endothelial
    damage.
  role: mediator
  cell_types:
  - preferred_term: Neutrophil
    term:
      id: CL:0000775
      label: neutrophil
  biological_processes:
  - preferred_term: Neutrophil chemotaxis
    modifier: INCREASED
    term:
      id: GO:0030593
      label: neutrophil chemotaxis
  - preferred_term: Reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  downstream:
  - target: Alveolar-Capillary Barrier Disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Oxidants, proteases, and inflammatory mediators injure epithelial and endothelial barrier cells.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Neutrophils are among the most important mediators of inflammation and
        lung tissue destruction during ARDS.
      explanation: >-
        The review identifies neutrophils as mediators of tissue destruction,
        supporting their placement upstream of barrier disruption.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During this process, multiple harmful mediators, including reactive oxygen
      species (ROS), proteases, and proinflammatory lipid mediators such as
      prostaglandins and leukotrienes, are released simultaneously.
    explanation: >-
      The review describes neutrophil transit and the damaging mediator classes
      that connect recruitment to barrier injury.
  - reference: PMID:37283946
    reference_title: Single-cell analysis reveals dysregulated inflammatory response in peripheral blood immunity in patients with acute respiratory distress syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In particular, a significant enhancement of the oxidative stress response
      was observed in the neutrophil subpopulation.
    explanation: >-
      Patient peripheral-blood single-cell and bulk transcriptomics provide
      human evidence for enhanced neutrophil oxidative-stress programs, while
      the small, etiology-specific sample limits generalization.
- name: Immunometabolic Reprogramming and Mitochondrial Dysfunction
  description: >-
    Immune and structural lung cells can shift toward glycolysis while
    mitochondrial oxidative phosphorylation and redox control deteriorate.
    Lactate, succinate, extracellular ATP, and mitochondrial danger signals may
    then act as signaling mediators that sustain inflammatory activation and
    impair energetically demanding barrier repair. This is modeled as an
    emerging modifier rather than a required step in every patient.
  role: modifier
  cell_types:
  - preferred_term: Alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  - preferred_term: Pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  genes:
  - preferred_term: NLRP3
    term:
      id: hgnc:16400
      label: NLRP3
  biological_processes:
  - preferred_term: Glycolytic process
    modifier: INCREASED
    term:
      id: GO:0006096
      label: glycolytic process
  - preferred_term: Oxidative phosphorylation
    modifier: DECREASED
    term:
      id: GO:0006119
      label: oxidative phosphorylation
  - preferred_term: Reactive oxygen species metabolic process
    modifier: INCREASED
    term:
      id: GO:0072593
      label: reactive oxygen species metabolic process
  downstream:
  - target: Alveolar-Capillary Barrier Disruption
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - immunometabolic_resilience_model
    description: >-
      Bioenergetic failure and metabolite signaling may amplify inflammatory
      injury and limit ATP-dependent epithelial and endothelial repair.
    evidence:
    - reference: PMID:42432720
      reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Beyond reflecting metabolic stress, these metabolites function as
        signalling mediators that are associated with amplified inflammatory
        pathways, compromised alveolar-capillary barrier integrity, and
        sustained lung injury.
      explanation: >-
        Association in a narrative synthesis supports this proposed edge only
        partially; the human causal intermediates remain unresolved.
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During acute lung injury, immune and structural lung cells undergo
      metabolic shifts characterized by increased glycolysis, impaired
      mitochondrial oxidative phosphorylation, and accumulation of bioactive
      metabolites such as lactate, succinate, and extracellular adenosine
      triphosphate (ATP).
    explanation: >-
      The review supports the specific metabolic changes represented in this
      emerging modifier node.
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Beyond reflecting metabolic stress, these metabolites function as
      signalling mediators that are associated with amplified inflammatory
      pathways, compromised alveolar-capillary barrier integrity, and sustained
      lung injury.
    explanation: >-
      The evidence is marked PARTIAL because the review describes association
      and mechanistic plausibility rather than proving this causal edge in an
      unselected human ARDS population.
- name: Ventilator-Induced Lung Injury
  conforms_to: "alveolar_capillary_barrier_failure#Cyclic Mechanical Strain Amplification"
  description: >-
    Positive-pressure ventilation can amplify established ARDS through
    overdistension, cyclic opening and closing, and patient-ventilator
    dyssynchrony. Lung-protective tidal volumes and, in selected early severe
    disease, neuromuscular blockade limit this iatrogenic stretch-injury loop.
  role: modifier
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Alveolar-Capillary Barrier Disruption
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      Excessive mechanical stress adds epithelial and endothelial injury to the
      pre-existing inflammatory permeability lesion.
    evidence:
    - reference: PMID:10793162
      reference_title: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Traditional approaches to mechanical ventilation use tidal volumes of
        10 to 15 ml per kilogram of body weight and may cause stretch-induced
        lung injury in patients with acute lung injury and the acute respiratory
        distress syndrome.
      explanation: >-
        The hedged ARMA trial rationale supports large-tidal-volume ventilation
        as a contributor to stretch-induced injury; PARTIAL avoids treating the
        background statement as definitive causal proof.
  evidence:
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      NMBAs are a commonly used adjunctive therapy for patients with ARDS (16,
      56). The mechanism of benefit is unclear, but likely involves decreasing
      ventilator-induced lung injury via a reduction in patient–ventilator
      dyssynchrony in addition to reducing oxygen consumption, inflammation,
      and alveolar fluid (57–59).
    explanation: >-
      The guideline explicitly recognizes ventilator-induced injury as an ARDS
      amplification mechanism and identifies dyssynchrony as one contributor.
- name: Alveolar-Capillary Barrier Disruption
  conforms_to: "alveolar_capillary_barrier_failure#Alveolar Epithelial and Endothelial Junctional Disruption"
  description: >-
    Injury to pulmonary capillary endothelial cells and pulmonary alveolar type
    1 and type 2 cells disrupts intercellular junctions, ion transport, and
    barrier selectivity. The resulting rise in vascular and epithelial
    permeability allows protein-rich fluid and inflammatory cells to enter the
    interstitium and alveolar space.
  role: mediator
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: Pulmonary alveolar type 1 cell
    term:
      id: CL:0002062
      label: pulmonary alveolar type 1 cell
  - preferred_term: Pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  biological_processes:
  - preferred_term: Positive regulation of vascular permeability
    modifier: INCREASED
    term:
      id: GO:0043117
      label: positive regulation of vascular permeability
  downstream:
  - target: Protein-Rich Alveolar Edema and Loss of Aerated Lung
    causal_link_type: DIRECT
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Increased barrier permeability permits fluid and protein to flood interstitial and alveolar compartments.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        During ARDS, fluid and protein pass through the alveolar epithelium due
        to increased permeability, leading to pulmonary interstitial edema.
      explanation: >-
        This directly supports permeability-driven fluid and protein movement
        into the injured lung.
  - target: Intra-Alveolar Coagulation and Fibrin Deposition
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      Injured alveolar epithelium sheds anticoagulant molecules and releases
      tissue factor, shifting the alveolar compartment toward coagulation.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The activation and damage of the alveolar epithelium can also lead to
        the shedding of anticoagulant molecules and the release of tissue
        factors from the lung epithelium into the alveolar space.
      explanation: >-
        The review supplies the epithelial-injury intermediates that connect
        barrier damage to local procoagulant activity.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Inflammatory dysregulation, inappropriate accumulation and activity of
      white blood cells and platelets, uncontrolled activation of coagulation
      pathways, and changes in the permeability of alveolar endothelial and
      epithelial barriers are the core pathological and physiological changes
      in acute lung injury and ARDS.
    explanation: >-
      The review identifies inflammatory, coagulation, endothelial, and
      epithelial barrier changes as core ARDS pathology.
- name: Intra-Alveolar Coagulation and Fibrin Deposition
  description: >-
    Loss of epithelial anticoagulant activity and local tissue-factor release
    promote procoagulant signaling and fibrin deposition within alveoli and near
    injured endothelium. Persistent fibrin-rich injury can contribute to
    disordered organization and fibroproliferative remodeling.
  role: mediator
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: Blood coagulation, fibrin clot formation
    modifier: INCREASED
    term:
      id: GO:0072378
      label: blood coagulation, fibrin clot formation
  downstream:
  - target: Fibroproliferative Remodeling and Fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      In nonresolving injury, fibrin-rich alveolar organization provides a
      provisional matrix and procoagulant milieu that can feed remodeling.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        driving the release of procoagulant factors and fibrin deposition in the
        alveoli as well as near endothelial cells.
      explanation: >-
        The review directly documents alveolar and peri-endothelial fibrin
        deposition; its contribution to later fibrosis is represented as an
        indirect, partially supported edge rather than a necessary outcome.
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      driving the release of procoagulant factors and fibrin deposition in the
      alveoli as well as near endothelial cells.
    explanation: >-
      The review directly supports local procoagulant-factor release and fibrin
      deposition in injured alveolar and endothelial compartments.
- name: Protein-Rich Alveolar Edema and Loss of Aerated Lung
  conforms_to: "alveolar_capillary_barrier_failure#Protein-Rich Alveolar Flooding and Gas-Exchange Failure"
  description: >-
    Increased permeability produces noncardiogenic interstitial and alveolar
    edema. Fluid-filled and gravity-dependent collapsed alveoli reduce the
    ventilated gas-exchange surface and contribute to low compliance without
    requiring elevated left-sided filling pressure.
  role: mediator
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  downstream:
  - target: Shunt Physiology and Hypoxemic Respiratory Failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Perfusion of fluid-filled or collapsed alveoli creates shunt and severe gas-exchange failure.
    evidence:
    - reference: PMID:37487152
      reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical hallmarks of ARDS are arterial hypoxemia and bilateral
        radiographic opacities associated with increased shunting, increased
        alveolar dead space, and decreased lung compliance.
      explanation: >-
        The consensus definition ties loss of aerated lung to shunt physiology
        and hypoxemic failure.
  - target: Resolution and Alveolar Repair
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      When the inciting injury and inflammation are controlled, macrophage
      programs, alveolar epithelial proliferation, ion transport, and barrier
      repair can clear edema and restore gas exchange.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        In the late stage of ARDS, anti-inflammatory cytokines secreted by
        selectively activated macrophages inhibit the inflammatory response,
        thereby promoting epithelial regeneration and alveolar structural
        remodeling.
      explanation: >-
        The review supports the transition from inflammatory alveolar injury to
        macrophage-associated epithelial regeneration and repair.
  - target: Fibroproliferative Remodeling and Fibrosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      In a subset with persistent injury or dysregulated repair, the injured
      alveolar compartment progresses toward fibroproliferative remodeling and
      structural fibrosis rather than resolution.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        By the time fibrosis occurs, in addition to traction bronchiectasis,
        large grid-like and small cystic changes may be observed in the lungs.
      explanation: >-
        The review documents structural change in the fibrotic phase; the entry
        limits this fate to nonresolving injury in a subset.
  - target: Noncardiogenic pulmonary edema
    causal_link_type: DIRECT
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      Protein-rich permeability edema is the tissue mechanism represented by
      the clinical pulmonary-edema phenotype.
    evidence:
    - reference: PMID:37487152
      reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The resulting injury leads to pulmonary edema from an increase in
        pulmonary vascular and alveolar epithelial permeability.
      explanation: >-
        The consensus model directly links increased permeability to pulmonary
        edema.
  - target: Bilateral pulmonary opacities
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: >-
      Bilateral edema, collapse, and loss of aeration produce the characteristic
      bilateral radiographic or ultrasound abnormalities.
    evidence:
    - reference: PMID:37487152
      reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical hallmarks of ARDS are arterial hypoxemia and bilateral
        radiographic opacities associated with increased shunting, increased
        alveolar dead space, and decreased lung compliance.
      explanation: >-
        The consensus definition connects loss-of-aeration physiology to the
        bilateral imaging phenotype.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The resulting injury leads to pulmonary edema from an increase in
      pulmonary vascular and alveolar epithelial permeability. In addition,
      gravity-dependent atelectasis contributes to a loss of aerated lung
      tissue.
    explanation: >-
      The global conceptual model links permeability edema and atelectasis to
      loss of aerated lung.
- name: Shunt Physiology and Hypoxemic Respiratory Failure
  description: >-
    Ventilation-perfusion mismatch and intrapulmonary shunt cause refractory
    arterial hypoxemia. Increased dead space and reduced respiratory-system
    compliance increase ventilatory demand and can culminate in acute
    respiratory failure requiring assisted ventilation.
  role: outcome
  biological_processes:
  - preferred_term: Respiratory gaseous exchange by respiratory system
    modifier: DECREASED
    term:
      id: GO:0007585
      label: respiratory gaseous exchange by respiratory system
  downstream:
  - target: Hypoxemia
    causal_link_type: DIRECT
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Intrapulmonary shunt and impaired gas exchange directly lower arterial oxygenation.
    evidence:
    - reference: PMID:37487152
      reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The clinical hallmarks of ARDS are arterial hypoxemia and bilateral
        radiographic opacities associated with increased shunting, increased
        alveolar dead space, and decreased lung compliance.
      explanation: >-
        The consensus definition directly associates shunting with arterial
        hypoxemia.
  - target: Acute hypoxemic respiratory failure
    causal_link_type: DIRECT
    hypothesis_groups:
    - alveolar_capillary_injury_model
    description: Severe shunt physiology culminates in acute hypoxemic respiratory failure.
    evidence:
    - reference: PMID:42432720
      reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ARDS is characterized by diffuse alveolar damage, increased
        alveolar-capillary permeability, and severe hypoxemic respiratory
        failure.
      explanation: >-
        The review explicitly identifies severe hypoxemic respiratory failure
        as the clinical endpoint of ARDS lung injury.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical hallmarks of ARDS are arterial hypoxemia and bilateral
      radiographic opacities associated with increased shunting, increased
      alveolar dead space, and decreased lung compliance.
    explanation: >-
      The consensus definition directly supports the terminal physiology and
      its clinical manifestations.
- name: Resolution and Alveolar Repair
  description: >-
    After control of the acute injury, pulmonary alveolar type 2 cell
    proliferation, macrophage-mediated inflammation resolution, restoration of
    ion transport, and epithelial-endothelial repair can clear edema and restore
    gas exchange.
  role: outcome
  cell_types:
  - preferred_term: Pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Alveolar macrophage
    term:
      id: CL:0000583
      label: alveolar macrophage
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Following early damage to the alveolar epithelium, ATII cells rapidly
      proliferate
    explanation: >-
      The review supports type 2 alveolar cell proliferation during the
      transition from injury into repair.
- name: Fibroproliferative Remodeling and Fibrosis
  description: >-
    When injury and repair remain dysregulated, fibroproliferative remodeling,
    traction bronchiectasis, volume loss, and fibrotic structural change can
    produce persistent respiratory impairment. This is a nonresolving fate in a
    subset, not an inevitable stage of ARDS.
  role: outcome
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      By the time fibrosis occurs, in addition to traction bronchiectasis, large
      grid-like and small cystic changes may be observed in the lungs.
    explanation: >-
      The review supports a distinct fibrotic structural fate while the entry
      preserves that it occurs only in a subset with nonresolving injury.
histopathology:
- name: Diffuse Alveolar Damage with Hyaline Membrane Formation
  description: >-
    ARDS histology can show intraalveolar edema, inflammation, hyaline membrane
    formation, and alveolar hemorrhage in a diffuse-alveolar-damage pattern.
    These findings are variable and are neither universal nor required for the
    clinical diagnosis.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Histological findings vary and often include intraalveolar edema,
      inflammation, hyaline membrane formation, and alveolar hemorrhage, often
      termed diffuse alveolar damage; however, these histological features are
      not always present and are not necessary for a clinical diagnosis of ARDS
      (26).
    explanation: >-
      The consensus document supports the characteristic diffuse-alveolar-damage
      pattern and directly supplies the non-universality and diagnostic caveat.
biochemical:
- name: Alveolar and circulating lactate
  presence: INCREASED
  context: >-
    Elevated lactate is an investigational, compartment-dependent marker and
    signaling mediator of glycolytic dominance and critical-illness stress; it
    is neither specific nor sufficient for ARDS diagnosis.
  biomarker_term:
    preferred_term: lactate
    term:
      id: CHEBI:24996
      label: lactate
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During acute lung injury, immune and structural lung cells undergo
      metabolic shifts characterized by increased glycolysis, impaired
      mitochondrial oxidative phosphorylation, and accumulation of bioactive
      metabolites such as lactate, succinate, and extracellular adenosine
      triphosphate (ATP).
    explanation: >-
      The review supports lactate accumulation but not its use as an
      ARDS-specific diagnostic biomarker, hence PARTIAL support.
- name: Alveolar succinate
  presence: INCREASED
  context: >-
    Succinate accumulation is an investigational local immunometabolic signal
    associated with disrupted mitochondrial metabolism; routine clinical
    measurement and ARDS-specific thresholds are not established.
  biomarker_term:
    preferred_term: succinate
    term:
      id: CHEBI:30031
      label: succinate(2-)
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      During acute lung injury, immune and structural lung cells undergo
      metabolic shifts characterized by increased glycolysis, impaired
      mitochondrial oxidative phosphorylation, and accumulation of bioactive
      metabolites such as lactate, succinate, and extracellular adenosine
      triphosphate (ATP).
    explanation: >-
      The review supports succinate accumulation, while the entry explicitly
      preserves the lack of validated clinical measurement thresholds.
phenotypes:
- category: Respiratory
  name: Hypoxemia
  description: >-
    Acute arterial hypoxemia is a defining physiologic manifestation and is
    severity-classified using PaO2:FiO2 or, under specified conditions,
    SpO2:FiO2.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The clinical hallmarks of ARDS are arterial hypoxemia and bilateral
      radiographic opacities associated with increased shunting, increased
      alveolar dead space, and decreased lung compliance.
    explanation: The consensus definition names arterial hypoxemia as a clinical hallmark.
- category: Respiratory
  name: Acute hypoxemic respiratory failure
  description: >-
    Severe impairment of pulmonary gas exchange can require high-flow oxygen,
    noninvasive support, or invasive mechanical ventilation.
  phenotype_term:
    preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      ARDS is characterized by diffuse alveolar damage, increased
      alveolar-capillary permeability, and severe hypoxemic respiratory failure.
    explanation: The review directly identifies severe hypoxemic respiratory failure.
- category: Respiratory
  name: Noncardiogenic pulmonary edema
  description: >-
    Permeability-mediated protein-rich alveolar edema is central and is not
    primarily attributable to cardiac failure or fluid overload.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The resulting injury leads to pulmonary edema from an increase in
      pulmonary vascular and alveolar epithelial permeability.
    explanation: The consensus model directly links permeability injury to pulmonary edema.
- category: Imaging
  name: Bilateral pulmonary opacities
  description: >-
    Bilateral loss of lung aeration is identified by chest radiography,
    computed tomography, or appropriately performed lung ultrasound and is not
    fully explained by effusions, atelectasis, or focal masses.
  phenotype_term:
    preferred_term: Pulmonary opacity
    term:
      id: HP:0031457
      label: Pulmonary opacity
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The committee agreed that chest imaging criteria should include bilateral
      radiologic (chest radiography or computed tomography) or ultrasound
      findings suggestive of loss of lung aeration that are not fully explained
      by effusions, atelectasis, or nodules/masses.
    explanation: >-
      The global definition specifies bilateral imaging abnormalities and the
      principal exclusions.
diagnosis:
- name: Global Consensus Clinical Diagnosis
  diagnosis_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  description: >-
    Diagnose ARDS when acute or worsening hypoxemic respiratory failure occurs
    within one week of a predisposing insult or new respiratory symptoms, with
    bilateral loss of lung aeration on radiography, CT, or qualified ultrasound,
    and edema not primarily explained by cardiac failure, fluid overload,
    collapse, effusion, or embolism. Hypoxemia can be identified by
    PaO2:FiO2 at or below 300 mm Hg or by SpO2:FiO2 at or below 315 when SpO2 is
    at or below 97%; the global definition includes specified nonintubated and
    resource-limited pathways.
  results: >-
    Acute bilateral noncardiogenic inflammatory lung injury with qualifying
    hypoxemia supports the diagnosis; severity and respiratory-support category
    should be recorded separately.
  evidence:
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The committee agreed that the current time frame for the diagnosis of ARDS
      should be retained: acute onset or worsening of hypoxemic respiratory
      failure is defined as occurring within 1 week of the onset of the
      predisposing risk factor or within 1 week of new or worsening respiratory
      symptoms.
    explanation: This establishes the acute diagnostic time window.
  - reference: PMID:37487152
    reference_title: A New Global Definition of Acute Respiratory Distress Syndrome.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      The committee made four main recommendations: 1) include high-flow nasal
      oxygen with a minimum flow rate of ⩾30 L/min; 2) use PaO2:FiO2 ⩽ 300 mm Hg
      or oxygen saturation as measured by pulse oximetry SpO2:FiO2 ⩽ 315 (if
      oxygen saturation as measured by pulse oximetry is ⩽97%) to identify
      hypoxemia; 3) retain bilateral opacities for imaging criteria but add
      ultrasound as an imaging modality, especially in resource-limited areas;
      and 4) in resource-limited settings, do not require positive
      end-expiratory pressure, oxygen flow rate, or specific respiratory support
      devices.
    explanation: >-
      The global definition supplies the oxygenation, imaging, and
      respiratory-support criteria represented in the diagnostic description.
treatments:
- name: Etiology-Directed and Intensive Supportive Care
  description: >-
    Identify and treat the precipitating cause while providing oxygenation,
    hemodynamic support, infection management when indicated, prevention of
    secondary injury, and organ support. ARDS has no single etiology-specific
    pharmacologic cure, so supportive strategies are selected by severity and
    patient context.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  evidence:
  - reference: PMID:39866839
    reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Given the complexity of the underlying disease, treatment needs to be
      tailored to the problem.
    explanation: >-
      The review supports etiology- and context-specific management of this
      heterogeneous syndrome.
- name: Lung-Protective Low-Tidal-Volume Mechanical Ventilation
  description: >-
    For invasively ventilated ARDS, use low tidal volumes based on predicted
    body weight and limit plateau pressure to reduce ventilator-induced stretch
    injury. The pivotal trial compared an initial 6 mL/kg predicted body weight
    and plateau pressure at or below 30 cm H2O with traditional larger volumes.
  treatment_term:
    preferred_term: mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  target_mechanisms:
  - target: Ventilator-Induced Lung Injury
    treatment_effect: INHIBITS
    description: >-
      Lower tidal volume and plateau-pressure limitation reduce injurious
      mechanical stretch during invasive ventilation.
    evidence:
    - reference: PMID:10793162
      reference_title: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Traditional approaches to mechanical ventilation use tidal volumes of
        10 to 15 ml per kilogram of body weight and may cause stretch-induced
        lung injury in patients with acute lung injury and the acute respiratory
        distress syndrome.
      explanation: >-
        The trial directly motivates lower-volume ventilation as prevention of
        stretch-induced lung injury.
  evidence:
  - reference: PMID:10793162
    reference_title: Ventilation with lower tidal volumes as compared with traditional tidal volumes for acute lung injury and the acute respiratory distress syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with acute lung injury and the acute respiratory distress
      syndrome, mechanical ventilation with a lower tidal volume than is
      traditionally used results in decreased mortality and increases the
      number of days without ventilator use.
    explanation: >-
      The multicenter randomized trial directly supports lung-protective
      lower-tidal-volume ventilation.
- name: Prolonged Prone Positioning for Severe ARDS
  description: >-
    Use early, prolonged prone sessions in appropriately selected patients with
    severe ARDS alongside lung-protective ventilation; the pivotal protocol used
    sessions of at least 16 hours.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_phenotypes:
  - preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  target_mechanisms:
  - target: Shunt Physiology and Hypoxemic Respiratory Failure
    treatment_effect: MODULATES
    description: >-
      Proning redistributes ventilation and perfusion and recruits dependent
      lung, thereby improving oxygenation across the shunt-dominated physiology.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        The prone position is a readily implementable intervention associated
        with improved oxygenation due to an increased ventilator–blood flow
        ratio, more uniform ventilation distribution, increased lung volume,
        and improved perfusion redistribution during partial alveolar
        re-expansion in the respiratory-dependent area of the lung.
      explanation: >-
        The review directly links prone positioning to redistribution of
        ventilation and perfusion and improved oxygenation.
  evidence:
  - reference: PMID:23688302
    reference_title: Prone positioning in severe acute respiratory distress syndrome.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      In patients with severe ARDS, early application of prolonged
      prone-positioning sessions significantly decreased 28-day and 90-day
      mortality.
    explanation: >-
      The randomized PROSEVA trial directly supports early prolonged proning in
      its severe-ARDS population.
- name: Conservative Fluid Management After Hemodynamic Stabilization
  description: >-
    Once shock and tissue hypoperfusion are addressed, a conservative fluid
    strategy can reduce hydrostatic contribution to lung edema and shorten
    ventilatory and ICU support. The pivotal trial improved lung function and
    ventilator-free days but did not significantly reduce 60-day mortality.
  treatment_term:
    preferred_term: fluid therapy
    term:
      id: NCIT:C116537
      label: Fluid Therapy
  target_phenotypes:
  - preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
  target_mechanisms:
  - target: Protein-Rich Alveolar Edema and Loss of Aerated Lung
    treatment_effect: INHIBITS
    description: >-
      After hemodynamic stabilization, conservative fluid management limits the
      fluid burden superimposed on permeability edema and improves lung
      function.
    evidence:
    - reference: PMID:16714767
      reference_title: Comparison of two fluid-management strategies in acute lung injury.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        Although there was no significant difference in the primary outcome of
        60-day mortality, the conservative strategy of fluid management
        improved lung function and shortened the duration of mechanical
        ventilation and intensive care without increasing nonpulmonary-organ
        failures.
      explanation: >-
        FACTT directly demonstrates improved lung function from the conservative
        strategy while retaining its neutral mortality result.
  evidence:
  - reference: PMID:16714767
    reference_title: Comparison of two fluid-management strategies in acute lung injury.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Although there was no significant difference in the primary outcome of
      60-day mortality, the conservative strategy of fluid management improved
      lung function and shortened the duration of mechanical ventilation and
      intensive care without increasing nonpulmonary-organ failures.
    explanation: >-
      The randomized FACTT trial supports conservative management for pulmonary
      and support-duration outcomes while preserving its neutral mortality result.
- name: Systemic Corticosteroids
  description: >-
    Systemic corticosteroids may be considered for ARDS, individualized to
    etiology, timing, infection risk, and adverse-effect profile. The current ATS
    recommendation is conditional and does not establish one molecule, dose, or
    duration for every patient.
  treatment_term:
    preferred_term: systemic corticosteroid therapy
    term:
      id: NCIT:C122080
      label: Systemic Corticosteroid Therapy
    therapeutic_agent:
    - preferred_term: corticosteroid
      term:
        id: CHEBI:50858
        label: corticosteroid
  target_mechanisms:
  - target: Alveolar Macrophage and Cytokine Activation
    treatment_effect: INHIBITS
    description: >-
      Corticosteroids suppress synthesis of proinflammatory mediators that
      sustain the macrophage-cytokine activation node.
    evidence:
    - reference: PMID:38032683
      reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        Corticosteroids are anti-inflammatory medications that inhibit the
        synthesis of proinflammatory mediators present in ARDS.
      explanation: >-
        The guideline directly states the anti-inflammatory mechanism used to
        join corticosteroid treatment to cytokine activation.
  evidence:
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We suggest the use of: 1) corticosteroids for patients with ARDS
      (conditional recommendation, moderate certainty of evidence)
    explanation: >-
      The official guideline supports corticosteroids while the entry preserves
      the recommendation's conditional strength.
- name: Higher PEEP Without Prolonged Recruitment Maneuvers
  description: >-
    In moderate-to-severe ARDS, higher positive end-expiratory pressure may be
    used to maintain recruitment as part of lung-protective ventilation, but
    prolonged lung recruitment maneuvers should be avoided.
  treatment_term:
    preferred_term: mechanical ventilation
    term:
      id: NCIT:C70909
      label: Mechanical Ventilation
  target_phenotypes:
  - preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  evidence:
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We suggest using higher PEEP without lung recruitment maneuvers (LRMs) as
      opposed to lower PEEP in patients with moderate to severe ARDS
      (conditional recommendation, low to moderate certainty).
    explanation: >-
      The guideline supports higher PEEP without recruitment maneuvers and
      states the low-to-moderate certainty explicitly.
- name: Neuromuscular Blockade for Early Severe ARDS
  description: >-
    Neuromuscular blockade may be considered early in selected patients with
    severe ARDS when deep sedation and ventilator synchrony are required. It is
    not routine treatment for all ARDS because the guideline recommendation is
    conditional and based on low-certainty evidence.
  treatment_term:
    preferred_term: neuromuscular blockade
    term:
      id: NCIT:C158070
      label: Neuromuscular Blockade
    therapeutic_agent:
    - preferred_term: cisatracurium
      term:
        id: CHEBI:140621
        label: cisatracurium
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  target_mechanisms:
  - target: Ventilator-Induced Lung Injury
    treatment_effect: INHIBITS
    description: >-
      In selected early severe ARDS, blockade can reduce patient-ventilator
      dyssynchrony and thereby limit ventilator-induced injury.
    evidence:
    - reference: PMID:38032683
      reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        NMBAs are a commonly used adjunctive therapy for patients with ARDS (16,
        56). The mechanism of benefit is unclear, but likely involves decreasing
        ventilator-induced lung injury via a reduction in patient–ventilator
        dyssynchrony in addition to reducing oxygen consumption, inflammation,
        and alveolar fluid (57–59).
      explanation: >-
        The guideline explicitly links neuromuscular blockade to reduced
        dyssynchrony and likely reduction of ventilator-induced injury.
  evidence:
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We suggest using neuromuscular blockade in patients with early severe ARDS
      (conditional recommendation, low certainty)
    explanation: >-
      The official guideline limits neuromuscular blockade to early severe ARDS
      and explicitly grades the recommendation as conditional and low certainty.
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Although this guideline does not recommend a specific NMBA, cisatracurium
      was used in the two largest RCTs (60, 64) and may be associated with
      pleiotropic effects, including a decrease in inflammatory cytokines (68,
      69), suggesting that it may be a preferable NMBA for patients with ARDS.
    explanation: >-
      The guideline supports cisatracurium as the best-studied representative
      agent while explicitly retaining that no specific NMBA is mandated.
- name: Venovenous Extracorporeal Membrane Oxygenation
  description: >-
    VV-ECMO is rescue organ support for carefully selected patients with severe,
    refractory ARDS after optimization of conventional lung-protective care.
    Patient selection, center expertise, reversibility, duration of ventilation,
    and complication risk are essential because certainty of benefit remains low.
  treatment_term:
    preferred_term: extracorporeal membrane oxygenation
    term:
      id: NCIT:C171507
      label: Extracorporeal Membrane Oxygenation
  target_phenotypes:
  - preferred_term: Respiratory failure
    term:
      id: HP:0002878
      label: Respiratory failure
  target_mechanisms:
  - target: Shunt Physiology and Hypoxemic Respiratory Failure
    treatment_effect: MODULATES
    description: >-
      VV-ECMO provides extracorporeal gas exchange while the injured lung is
      supported, improving blood oxygen exchange in refractory respiratory
      failure without claiming to repair the upstream alveolar lesion.
    evidence:
    - reference: PMID:39866839
      reference_title: "Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies."
      supports: SUPPORT
      evidence_source: OTHER
      snippet: >-
        ECMO directly provides conditional support for patients, improves the
        blood oxygen exchange rate, and has an important impact on the
        adjustment of body hemodynamics.
      explanation: >-
        The review directly links ECMO support to improved blood oxygen exchange,
        supporting a conservative MODULATES edge to terminal shunt physiology.
  evidence:
  - reference: PMID:38032683
    reference_title: "An Update on Management of Adult Patients with Acute Respiratory Distress Syndrome: An Official American Thoracic Society Clinical Practice Guideline."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      We suggest using venovenous extracorporeal membrane oxygenation (VV-ECMO)
      in selected patients with severe ARDS (conditional recommendation, low
      certainty of evidence).
    explanation: >-
      The official guideline supports VV-ECMO only for selected severe cases and
      explicitly grades the evidence as low certainty.
discussions:
- discussion_id: disc_ards_metabolic_endotype_validation
  prompt: >-
    Do longitudinal immunometabolic states causally define reproducible ARDS
    endotypes that predict recovery and treatment response, and can metabolic
    resilience be measured prospectively well enough to guide therapy?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Immunometabolic Reprogramming and Mitochondrial Dysfunction
  rationale: >-
    PMID:42432720 synthesizes glycolytic shifts, impaired oxidative
    phosphorylation, metabolite signaling, and mitochondrial dysfunction into a
    metabolic-resilience framework. However, it is a narrative review, human
    multi-omic studies are largely associative and compartment-dependent, and
    some longitudinal claims are extrapolated from sepsis or experimental acute
    lung injury. Prospective ARDS-specific validation is needed to establish
    whether these metabolic states are causal, stable enough for bedside
    classification, and predictive of benefit from a metabolism-targeted
    intervention rather than merely markers of severity.
  evidence:
  - reference: PMID:42432720
    reference_title: "Immunometabolic reprogramming and mitochondrial dysfunction in acute respiratory distress syndrome: mechanisms, metabolic resilience, and therapeutic perspectives- a narrative review."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Multi-omic studies further demonstrate that distinct metabolic signatures
      are associated with ARDS phenotypes, disease severity, and treatment
      responsiveness.
    explanation: >-
      The association of metabolic signatures with phenotype and response is the
      evidence base that motivates, but does not resolve, the prospective causal
      and treatment-selection question.
datasets: []

experimental_models:
- name: Human airway-on-a-chip chlorine gas exposure model
  description: >-
    A microfluidic human airway chip with pseudostratified mucociliary
    epithelium, a biomimetic extracellular matrix hydrogel, an endothelial
    compartment, and integrated electrodes for transepithelial electrical
    resistance, coupled to a chlorine generation and delivery platform that
    controls concentration and exposure duration precisely. Transcriptomics and
    metabolomics were run across post-exposure timepoints. It addresses a gap
    that is unusually hard to fill any other way: human clinical data on acute
    chlorine exposure are scarce for obvious reasons, and animal models translate
    poorly.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: epithelium of bronchus
    term:
      id: UBERON:0002031
      label: epithelium of bronchus
  cell_types:
  - preferred_term: Bronchial epithelial cell
    term:
      id: CL:0002328
      label: bronchial epithelial cell
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  conditions:
  - chlorine gas 10, 20, and 30 ppm for 10 to 30 minutes
  - medical air exposure control
  culture_system: Microfluidic airway-on-a-chip at air-liquid interface with integrated TEER electrodes
    and controlled gas exposure
  publication: PMID:41442163
  modeled_mechanisms:
  - target: Direct Pulmonary or Indirect Systemic Insult
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Delivers a graded, precisely metered inhalational chemical insult to human
      airway tissue, with a dose-response spanning recoverable injury at 10 ppm
      through irreversible barrier loss at 30 ppm.
    limitations: >-
      Chlorine is one specific inhalational insult and the chip is bronchial
      rather than alveolar, so it models the direct pulmonary insult category
      only for inhaled oxidant gases and not for aspiration, pneumonia, or the
      indirect systemic insults that cause most ARDS.
    readouts:
    - name: Transepithelial electrical resistance across chlorine dose and duration
      target: Direct Pulmonary or Indirect Systemic Insult
      direction: DECREASED
      interpretation: >-
        A recoverable-to-irreversible dose-response identifies the threshold at
        which an inhalational insult becomes an established barrier lesion.
      evidence:
      - reference: PMID:41442163
        reference_title: A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Transepithelial electrical resistance (TEER) measurements of barrier function also showed
          recoverable function at 10 ppm Cl2, progressing to a critical loss of barrier function at higher
          concentrations or exposure durations.
        explanation: Reports the graded barrier response to the insult this node describes.
    evidence:
    - reference: PMID:41442163
      reference_title: A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: Epithelial barrier disruption, characterized by gap formation, was evident immediately post-Cl2
        exposure and persisted through 24 h
      explanation: Supports the chip as a model of a direct pulmonary chemical insult producing sustained
        injury.
  - target: Alveolar-Capillary Barrier Disruption
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Epithelial junctional gaps appeared immediately after exposure, and
      endothelial junctional disruption followed only at 72 hours despite the
      endothelium never being directly exposed. The delay is the point: it
      establishes that barrier injury propagates from the epithelial to the
      endothelial layer rather than both being independently damaged.
    limitations: >-
      The chip has no neutrophils or macrophages, so the inflammatory
      amplification and resolution phases that dominate barrier disruption in
      clinical ARDS are represented only indirectly through early
      epithelial-endothelial signalling. It is also airway rather than alveolar
      epithelium.
    readouts:
    - name: Endothelial VE-cadherin junction integrity at 72 hours post-exposure
      target: Alveolar-Capillary Barrier Disruption
      direction: DECREASED
      interpretation: >-
        Delayed endothelial junctional loss after an exclusively epithelial
        exposure is evidence of trans-barrier propagation.
      evidence:
      - reference: PMID:41442163
        reference_title: A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: In contrast, endothelial junction disruption emerged at 72 h, supporting secondary endothelial
          dysfunction following epithelial oxidative injury.
        explanation: Directly reports the delayed, secondary endothelial injury this readout measures.
    evidence:
    - reference: PMID:41442163
      reference_title: A human airway-on-a-chip microphysiological system for modeling chlorine gas toxicity.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: A primary constraint is the absence of innate immune system components, limiting evaluation
        of inflammatory responses to early epithelial/endothelial signaling that would typically recruit
        neutrophils and macrophages.
      explanation: The authors' own statement of the model's key limitation for a node whose clinical
        form is inflammation-driven; PARTIAL records informative but bounded relevance.
- name: Organoid-derived Pseudomonas pneumonia-on-a-chip (VAP) model
  description: >-
    An alveolus chip lined with organoid-derived alveolar epithelial cells that
    differentiate into both type 2 and type 1-like cells, plus primary pulmonary
    microvascular endothelium, cycled at a respiratory-like 0.25 Hz at either
    physiological (5%) or hyperphysiological (10%) strain and infected with
    Pseudomonas aeruginosa. Comparing the two strain levels under an otherwise
    identical infection isolates the contribution of ventilation-associated
    stretch, which is the central question in ventilator-associated pneumonia and
    ventilator-induced lung injury.
  experimental_model_type: ORGAN_ON_CHIP
  namo_type: namo:OrganOnChip
  organism:
    preferred_term: human
    term:
      id: NCBITaxon:9606
      label: Homo sapiens
  tissue_term:
    preferred_term: alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: Pulmonary alveolar type 2 cell
    term:
      id: CL:0002063
      label: pulmonary alveolar type 2 cell
  - preferred_term: Pulmonary alveolar type 1 cell
    term:
      id: CL:0002062
      label: pulmonary alveolar type 1 cell
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  conditions:
  - physiological cyclic strain (5%, 0.25 Hz)
  - hyperphysiological cyclic strain (10%, 0.25 Hz)
  - Pseudomonas aeruginosa PAO1 infection
  cell_source: Human alveolar organoid-derived epithelial cells and primary pulmonary microvascular
    endothelial cells
  culture_system: Alveolus-on-a-chip with air-liquid interface, vascular flow, and controlled cyclic strain
  publication: PMID:41252215
  modeled_mechanisms:
  - target: Ventilator-Induced Lung Injury
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Raising cyclic strain from physiological to hyperphysiological levels
      increased apparent permeability and, under infection, increased bacterial
      counts in the vascular channel. This reproduces the clinical interaction in
      which ventilation-associated overdistension worsens an infectious insult
      rather than merely coexisting with it.
    limitations: >-
      Uniform cyclic strain across a chip membrane is not the regionally
      heterogeneous overdistension and cyclic recruitment-derecruitment of an
      injured ventilated lung, and the model has no immune cells, so the
      leukocyte-mediated component of ventilator-induced injury is absent.
      Readouts are at 12 hours post-infection only.
    readouts:
    - name: Apparent permeability under hyperphysiological versus physiological strain
      target: Ventilator-Induced Lung Injury
      direction: INCREASED
      interpretation: >-
        Strain-dependent permeability increase is the barrier readout for
        stretch injury.
      evidence:
      - reference: PMID:41252215
        reference_title: Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip
          model.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: "Yet, Papp was slightly increased in 10% stretched ODAECs, suggesting barrier impairment
          by hyperphysiological stretch."
        explanation: Reports the permeability effect of strain alone; PARTIAL preserves the authors'
          description of the effect as slight.
    - name: Bacterial translocation to the vascular channel under increased strain
      target: Ventilator-Induced Lung Injury
      direction: INCREASED
      interpretation: >-
        Higher vascular-channel colony counts under greater strain quantify the
        strain-infection interaction.
      evidence:
      - reference: PMID:41252215
        reference_title: Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip
          model.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Notably, increased cellular stretch intensified Pseudomonas infection, leading to greater
          barrier disruption and bacterial translocation
        explanation: Directly reports increased barrier disruption and translocation under greater
          strain.
    evidence:
    - reference: PMID:41252215
      reference_title: Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip
        model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We hereby present what we believe to be the first functional Pseudomonas POC and VAP-on-a-chip
        model that replicates key features of disease, including enhanced mechanical strain.
      explanation: Supports the chip as a model of ventilator-associated infectious lung injury, the
        clinical setting this node describes.
  - target: Alveolar-Capillary Barrier Disruption
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Infection combined with hyperphysiological strain disrupted the
      alveolar-capillary barrier and allowed bacteria to cross into the vascular
      compartment, reproducing the permeability lesion together with its
      functional consequence.
    limitations: >-
      Barrier failure is measured as apparent permeability and bacterial
      translocation over 12 hours, without the protein-rich alveolar flooding,
      coagulation, or leukocyte transmigration that accompany the lesion
      clinically.
    readouts:
    - name: Barrier disruption with bacterial translocation
      target: Alveolar-Capillary Barrier Disruption
      direction: INCREASED
      interpretation: >-
        Passage of bacteria from the alveolar to the vascular channel is a
        functional demonstration that the barrier has failed.
      evidence:
      - reference: PMID:41252215
        reference_title: Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip
          model.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Notably, increased cellular stretch intensified Pseudomonas infection, leading to greater
          barrier disruption and bacterial translocation
        explanation: Reports barrier disruption with translocation as a combined functional readout.
    evidence:
    - reference: PMID:41252215
      reference_title: Mechanical strain exacerbates Pseudomonas infection in an organoid-based pneumonia-on-a-chip
        model.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: We hereby present what we believe to be the first functional Pseudomonas POC and VAP-on-a-chip
        model that replicates key features of disease, including enhanced mechanical strain.
      explanation: Supports the chip as informative for the alveolar-capillary barrier lesion under
        combined infectious and mechanical insult.
📚

References & Deep Research

Deep Research

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Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Respiratory Distress Syndrome. Core disease mechanisms, molecular an...
Asta Scientific Corpus Retrieval 20 citations 2026-08-08T12:10:49.945606

Asta Literature Retrieval: Pathophysiology and clinical mechanisms of Acute Respiratory Distress Syndrome. Core disease mechanisms, molecular an...

This report is retrieval-only and is generated directly from Asta results.

  • Papers retrieved: 20
  • Snippets retrieved: 20

Relevant Papers

[1] Lung regeneration: diverse cell types and the therapeutic potential

  • Authors: Yutian Chen, Zhen Li, Gaili Ji, Shaochi Wang, Chunheng Mo et al.
  • Year: 2024
  • Venue: MedComm
  • URL: https://www.semanticscholar.org/paper/0fbe00de4b129b66ffcc63fd4298d45dc0352a8c
  • DOI: 10.1002/mco2.494
  • PMID: 38405059
  • PMCID: 10885188
  • Citations: 30
  • Summary: A review of the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.
  • Evidence snippets:
  • Snippet 1 (score: 0.502) > Abstract Lung tissue has a certain regenerative ability and triggers repair procedures after injury. Under controllable conditions, lung tissue can restore normal structure and function. Disruptions in this process can lead to respiratory system failure and even death, causing substantial medical burden. The main types of respiratory diseases are chronic obstructive pulmonary disease (COPD), idiopathic pulmonary fibrosis (IPF), and acute respiratory distress syndrome (ARDS). Multiple cells, such as lung epithelial cells, endothelial cells, fibroblasts, and immune cells, are involved in regulating the repair process after lung injury. Although the mechanism that regulates the process of lung repair has not been fully elucidated, clinical trials targeting different cells and signaling pathways have achieved some therapeutic effects in different respiratory diseases. In this review, we provide an overview of the cell type involved in the process of lung regeneration and repair, research models, and summarize molecular mechanisms involved in the regulation of lung regeneration and fibrosis. Moreover, we discuss the current clinical trials of stem cell therapy and pharmacological strategies for COPD, IPF, and ARDS treatment. This review provides a reference for further research on the molecular and cellular mechanisms of lung regeneration, drug development, and clinical trials.

[2] Acute respiratory distress syndrome (ARDS): from mechanistic insights to therapeutic strategies

  • Authors: Rongli Xie, Dan Tan, Boke Liu, Guohui Xiao, Fangchen Gong et al.
  • Year: 2025
  • Venue: MedComm
  • URL: https://www.semanticscholar.org/paper/97d3e572d53d14edaa3fdb78fe49b51047c7aabc
  • DOI: 10.1002/mco2.70074
  • PMID: 39866839
  • PMCID: 11769712
  • Citations: 33
  • Influential citations: 1
  • Summary: The pathogenesis and treatment methods of affected organs, including 2019 coronavirus disease (COVID‐19)‐related pneumonia, drowning, trauma, blood transfusion, severe acute pancreatitis, and sepsis are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.491) > Acute respiratory distress syndrome (ARDS) is a clinical syndrome of acute hypoxic respiratory failure caused by diffuse lung inflammation and edema. The mortality rate is high in ARDS patients and is related to the severity of the patient's condition. 1 ARDS can be precipitated by intrapulmonary factors (pneumonia, aspiration, etc.) or extrapulmonary factors (severe acute pancreatitis [SAP], sepsis, trauma, etc.), which can lead to severe hypoxemia, decreased lung compliance, increased arteriovenous shunts, and increased physiological dead space. 4][5] Each revision of the definition, in response to new research findings and clinical concepts, is intended to provide a definition that consistently and accurately identifies patients. The pathophysiology of ARDS is complex and involves the activation and dysregulation of multiple overlapping and interacting pathways of systemic inflammation and coagulation, including the respiratory, circulatory, and immune systems. In general, the treatment of inflammatory injuries is a coordinated process that involves the downregulation of proinflammatory pathways and the upregulation of anti-inflammatory pathways. Owing to differences in etiology and inducement, there is heterogeneity in the clinical syndrome. In recent years, foundation medicine, radiology, immunology, and other disciplines have increasingly recognized and incorporated phenotype recognition. > ARDS is a highly heterogeneous disease with different etiologies, different inflammatory phenotypes and different histomorphologic characteristics, which leads to relatively slow progress in the treatment of ARDS. Individualized medical approaches to the etiology of ARDS can improve the identification of ARDS phenotypes, which should contribute to a better understanding of its pathophysiological mechanisms and differences between patients. In this review, we discuss the current understanding of the structural features and changes in the lung function of ARDS patients. We further discuss the pathogenesis and treatment methods of affected organs according to their different causes.

[3] A practical approach to adult acute respiratory distress syndrome

  • Authors: C. Manthous
  • Year: 2010
  • Venue: Indian Journal of Critical Care Medicine : Peer-reviewed, Official Publication of Indian Society of Critical Care Medicine
  • URL: https://www.semanticscholar.org/paper/affa7b3f3d93c8318e50fb89eabdce8c86696a23
  • DOI: 10.4103/0972-5229.76084
  • PMID: 21572751
  • PMCID: 3085221
  • Citations: 4
  • Summary: The clinical features and how pathophysiology informs the evidence-based management of ARDS are reviewed, which shows how the disease has carried a very high mortality.
  • Evidence snippets:
  • Snippet 1 (score: 0.489) > Acute respiratory distress syndrome (ARDS) is a common disease encountered in hospitalized adult patients that, historically, has carried a very high mortality. This article reviews the clinical features and how pathophysiology informs the evidence-based management of ARDS.

[4] Genetic and Multi‐Omics Insights Into Monocyte Pantothenate‐Mediated Protection in Acute Respiratory Distress Syndrome

  • Authors: Yang Wang, Hongyu Sun, Fengying Liang, Y. Qian, Yuanyuan Wang et al.
  • Year: 2025
  • Venue: Journal of Cellular and Molecular Medicine
  • URL: https://www.semanticscholar.org/paper/475776c4266e5af912ab92f23bff48fd16d5fd2c
  • DOI: 10.1111/jcmm.70812
  • PMID: 41059665
  • PMCID: 12505201
  • Citations: 4
  • Summary: This study uses Mendelian randomisation, multi‐omics and machine learning approaches to provide novel insights into the pathogenesis of ARDS and its potential therapeutic strategies targeting monocyte metabolism and function.
  • Evidence snippets:
  • Snippet 1 (score: 0.467) > Acute respiratory distress syndrome (ARDS) is a severe and life-threatening condition characterised by rapid onset of widespread inflammation and increased permeability of the alveolar-capillary barrier, leading to impaired gas exchange and respiratory failure [1,2]. Despite advances in supportive care, including lung-protective ventilation strategies and neuromuscular blockade, the mortality rate for ARDS remains high, ranging from 30% to 45% [3]. This persistent mortality burden highlights the critical need for a deeper understanding of the underlying pathophysiology to inform the development of more effective therapeutic interventions. > Emerging evidence suggests that metabolic factors may play a crucial role in the pathogenesis of ARDS, though the precise mechanisms remain incompletely understood [4,5]. Alterations in cellular metabolism, including impaired energy production, oxidative stress and dysregulated signalling pathways, have been implicated in the initiation and progression of ARDS [6,7]. Furthermore, metabolic disturbances, such as hyperglycemia, dyslipidaemia and mitochondrial dysfunction, have been associated with worse clinical outcomes in ARDS patients [8][9][10][11]. However, the specific metabolic pathways and mediators involved in the development and resolution of ARDS remain poorly defined [12]. Continued research is necessary to elucidate this complex interplay between metabolism and the pathogenesis of ARDS, which may lead to the identification of novel therapeutic targets and the development of more personalised treatment strategies. > In this study, we aim to investigate the causal relationship between plasma metabolites, immune cell profiles and the risk of ARDS using Mendelian randomisation (MR) analysis. We integrate single-cell sequencing and transcriptomic data to explore the potential mechanisms underlying these associations. Additionally, we employ machine learning approaches to evaluate the predictive performance of a comprehensive set of risk factors for ARDS development. By elucidating the causal pathways and underlying biological mechanisms linking these metabolic and immune factors to ARDS, our research is expected to provide important insights into the pathogenesis of this devastating syndrome.

[5] Obesity promotes ARDS by modulating ceramide transfer protein-ceramide pathway and exacerbating oxidative stress/apoptosis in alveolar macrophages

  • Authors: Yichan Ao, Jingyue Ma, Xiangyu Hou, Hongbin Li, Zhiqiao Wang et al.
  • Year: 2025
  • Venue: Cellular and Molecular Life Sciences: CMLS
  • URL: https://www.semanticscholar.org/paper/23ee5a5309e9b3ceefad8175244fc04a35dbb765
  • DOI: 10.1007/s00018-025-05706-9
  • PMID: 40537702
  • PMCID: 12179041
  • Citations: 4
  • Summary: In vivo and in vitro studies indicated that obesity-induced downregulation of CERT reduced Cer transport, increased Cer levels, and aggravated ARDS through elevated ROS production and apoptosis, highlighting CERT may represent a promising therapeutic target for managing ARDS in individuals with obesity.
  • Evidence snippets:
  • Snippet 1 (score: 0.461) > Acute respiratory distress syndrome (ARDS) is a common critical condition characterized by acute respiratory distress and progressive hypoxemia, with its pathogenesis not yet fully understood. Approximately 10.4% of patients in intensive care units (ICUs) develop ARDS, a condition associated with high morbidity and mortality [1]. Obesity, a systemic chronic low-grade inflammatory state, is a wellestablished risk factor for various respiratory diseases [2]. Notably, obesity has been identified as an independent risk factor for the development of ARDS in ICU patients, with the risk nearly doubling in obese individuals [3][4][5]. Despite growing evidence that obesity increases susceptibility to ARDS and worsens disease severity, the mechanisms by which obesity contributes to the onset and progression of ARDS remain poorly understood. Therefore, animal models and basic research that reflect clinical characteristics are crucial for elucidating the specific mechanisms linking obesity and ARDS, potentially laying the groundwork for improving ARDS treatment outcomes [6][7][8][9]. > Multiple studies have demonstrated that "omics" strategies significantly contribute to understanding the pathophysiological pathways underlying diseases. Proteins, as the primary executors of biological functions, represent the final products of genetic information, while metabolites are essential components of cellular processes, participating in enzyme-catalyzed reactions critical for cell function. Quantitative proteomics allows for detailed characterization of pathogenic biochemical processes by measuring protein levels and their regulatory chemical modifications [10]. Additionally, metabolomics provides a wealth of information that strongly predicts phenotypic outcomes [11]. In recent years, these strategies have become valuable tools for exploring the etiology and mechanisms of obesity-related diseases [12][13][14][15]. In acute lung injury (ALI) or ARDS, various candidate biomarkers have been identified through the assessment of protein expression in lung tissues [16][17][18]. Moreover, integrated proteomics and metabolomics analyses have facilitated the identification of mechanisms relevant to drugs aimed at preventing or ameliorating ALI/ARDS [19]. However, specific changes in the protein and metabolite profiles associated with ARDS in HFD mice have yet to be characterized.

[6] Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome

  • Authors: Jane E Whitney, In‐Hee Lee, Ji-Won Lee, S. Kong
  • Year: 2022
  • Venue: eLife
  • URL: https://www.semanticscholar.org/paper/6d82effd3fff4275e47d52ecd0b92ee996e2ac37
  • DOI: 10.7554/eLife.77405
  • PMID: 35913450
  • PMCID: 9342956
  • Citations: 5
  • Summary: Novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.
  • Evidence snippets:
  • Snippet 1 (score: 0.453) > Pediatric acute respiratory distress syndrome (PARDS), though both common and deadly in critically ill children, lacks targeted therapies. The development of effective pharmacotherapies has been limited, in part, by lack of clarity about the pathobiology of pediatric ARDS. Epithelial lung injury, vascular endothelial activation, and systemic immune activation are putative drivers of this complex disease process. Prior studies have used either hypothesis-driven (e.g., candidate genes and proteins, in vitro investigations) or unbiased (e.g., genome-wide association, transcriptomic, metabolomic) approaches to predict clinical outcomes and to define subphenotypes. Advances in multiple omics technologies, including genomics, transcriptomics, proteomics, and metabolomics, have permitted more comprehensive investigation of PARDS pathobiology. However, omics studies have been limited in children compared to adults, and analyses across multiple tissue types are lacking. Here, we synthesized existing literature on the molecular mechanism of PARDS, summarized our interrogation of publicly available genomic databases to determine the association of candidate genes with PARDS phenotypes across multiple tissues and cell types, and integrated recent studies that used single-cell RNA sequencing (scRNA-seq). We conclude that novel profiling methods such as scRNA-seq, which permits more comprehensive, unbiased evaluation of pathophysiological mechanisms across tissue and cell types, should be employed to investigate the molecular mechanisms of PRDS toward the goal of identifying targeted therapies.

[7] Classic Signaling Pathways in Alveolar Injury and Repair Involved in Sepsis-Induced ALI/ARDS: New Research Progress and Prospect

  • Authors: Wenli Li, Duo Li, Yuansen Chen, Halidan Abudou, Haiwang Wang et al.
  • Year: 2022
  • Venue: Disease Markers
  • URL: https://www.semanticscholar.org/paper/4268a462890d48f33ce3908d40f66ecb9f3dd801
  • DOI: 10.1155/2022/6362344
  • PMID: 35726235
  • PMCID: 9206211
  • Citations: 127
  • Influential citations: 3
  • Summary: The signaling pathways related to alveolar injury and repair in sepsis-induced ALI/ARDS and their latest research progress include the NF-κB, JAK2/STAT3, mitogen-activated protein kinase (MAPK), mTOR, and Notch signaling pathways.
  • Evidence snippets:
  • Snippet 1 (score: 0.449) > Sepsis is a common critical clinical disease with high mortality that can cause approximately 10 million deaths worldwide each year. Acute lung injury (ALI) or acute respiratory distress syndrome (ARDS) is a common clinical complication of sepsis, which occurs primarily as diffuse alveolar injury, hypoxemia, and respiratory distress. The mortality rate of ALI/ARDS is as high as 30%-40%, which greatly endangers human health. Due to the unclear pathogenesis of ALI/ARDS, its treatment is still a worldwide problem. At present, clinical treatment mainly relies on lung-protective ventilation, prone position ventilation, and fluid management. However, there is a lack of effective and specific treatment measures. In recent years, domestic and foreign scholars have committed to basic research on ALI/ARDS, trying to further clarify its pathogenesis and find new targets and methods for the treatment of ALI/ARDS. In this review, we summarize the signaling pathways related to alveolar injury and repair in sepsis-induced ALI/ARDS and their latest research progress. They include the NF-κB, JAK2/STAT3, mitogen-activated protein kinase (MAPK), mTOR, and Notch signaling pathways. Understanding the molecular mechanisms of these signaling pathways in sepsis-induced ALI/ARDS may provide new targets and ideas for the clinical treatment of this disease.

[8] Acute Respiratory Failure: Pathophysiological Basis From A Multidisciplinary Clinical Approach

  • Authors: R. Castillo
  • Year: 2015
  • Venue: The Open Respiratory Medicine Journal
  • URL: https://www.semanticscholar.org/paper/f4537439b4e55e4efb383f03c5c3f561d9fcedf8
  • DOI: 10.2174/1874306401509010081
  • PMID: 26312098
  • PMCID: 4541451
  • Citations: 1
  • Summary: The evidence strongly supports its use in patients with chronic obstructive pulmonary disease (COPD) exacerbation, patients with acute cardiogenic pulmonary edema and immunosuppressed patients, and patients with hypoxemic and hypercapnic failure.
  • Evidence snippets:
  • Snippet 1 (score: 0.443) > Acute Respiratory Failure: Pathophysiological Basis from a Multidisciplinary Clinical Approach > Acute Respiratory Failure (ARF) is a syndrome characterized by the inability of the respiratory system to maintain adequate arterial O2 and CO2 levels according to the demands of cellular metabolism. ARF may be caused by the failure of the exchanger, lung, organ or pump, or failure of the respiratory muscles. ARF can be classified by the dysfunctional element or the evolution time when the condition occurs. > Acute lung injury/acute respiratory distress syndrome (ALI/ARDS) is the most important cause of adults hipoxemic respiratory failure, which results from multiple clinical factors such as sepsis or trauma [1]. Although the main cause was clinically resolved, the mechanism that determines the progression may persist and lead to complications. > However, It is demonstrated that the clinical causes of respiratory failure increase the intensive care units (ICU) stay, the sanitary cost and the global mortality [2]. For this reason, multidisciplinary and pathophysiological focus on respiratory failure is necessary for the management of these patients. > The application of non-invasive mechanical ventilation (NIMV) has acquired major relevance in the last few years in the management of ARF, in patients with hypoxemic and hypercapnic failure. The main advantage of NIMV compared to invasive mechanical ventilation is that it can be used earlier outside ICU. The evidence strongly supports its use in patients with chronic obstructive pulmonary disease (COPD) exacerbation, patients with acute cardiogenic pulmonary edema and immunosuppressed patients. > This issue is focused on the mechanism associated with ARF, some clinical syndromes, and the pathophysiological bases for the use of ventilatory strategies, with a multidisciplinary approach.

[9] Messenger RNA sequencing reveals similar mechanisms between neonatal and acute respiratory distress syndrome

  • Authors: H. Mei, Yuheng Zhang, Chun-zhi Liu, Yayu Zhang, Chunli Liu et al.
  • Year: 2017
  • Venue: Molecular Medicine Reports
  • URL: https://www.semanticscholar.org/paper/663e1561706e158cfc150ce2f69d0b6a184888e4
  • DOI: 10.3892/mmr.2017.7891
  • PMID: 29115600
  • PMCID: 5780146
  • Citations: 8
  • Summary: Using peripheral blood obtained from mature infants with and without NRDS and in tandem with mRNA sequencing, the present study identified that, while cell cycle regulation and alveolar surfactants serve a role in deterring the further onset of NRDS, innate and pathogen-induced responses of the immune system are among the most important factors in the pathology.
  • Evidence snippets:
  • Snippet 1 (score: 0.441) > Neonatal respiratory distress syndrome (NRDS), also termed hyaline membrane disease, is one of the most prevalent causes of morbidity and mortality in newborns (1). The oxygen diffusion efficiency through the alveoli-capillary exchange barrier is impacted by the dysregulation of numerous factors, leading to the pathophysiology of NRDS (2). Cellular stress at the gas-blood level is associated with alterations in alveolar surfactant proteins (3) and the upregulation of numerous innate immune responses of pro-inflammatory cytokines to foreign challenges (4). A lack of surfactant may drive the pathogenesis towards NRDS, while surfactant replacement therapy may mitigate symptoms of the disease by decreasing the surface tension of alveoli and facilitating their inflation (5,6). However, surfactant serves an additional role in immunological processes. A recent study demonstrated that applying clinical surfactant for patients led to a stronger response to challenges from foreign microbiota (7). Additionally, animal-derived surfactant applied for clinical use in humans has been demonstrated to be of use against lung pathogens and to mediate excess host damage from neutrophils (8). Therefore, it may be hypothesized that mechanisms that mechanisms of NRDS involving surfactant exert additional functions to promoting alveolar inflation. > Acute respiratory distress syndrome (ARDS) is a clinical phenotype precipitated by the manifestation of a severe form of lung injury due to numerous lung insults (9). The pathophysiological manifestation of ARDS is derived from a cascade that is triggered by the complex combination of risk factors, including asthma, sepsis, pneumonia, increased neutrophil presence in the lungs and other variables; accumulation of these numerous systemic factors forms the pathological endpoint of ARDS (10). > The present study used peripheral blood obtained from infants with (n=4) or without (n=2) NRDS in tandem with mRNA-sequencing (mRNA-seq) analysis to reveal various factors involved in the mechanisms of NRDS, and to compare onset mechanisms between NRDS and ARDS.

[10] NR4A1 Promotes LPS-Induced Acute Lung Injury through Inhibition of Opa1-Mediated Mitochondrial Fusion and Activation of PGAM5-Related Necroptosis

  • Authors: Pingjun Zhu, Junyan Wang, Wenjuan Du, Jun Ren, Ying Zhang et al.
  • Year: 2022
  • Venue: Oxidative Medicine and Cellular Longevity
  • URL: https://www.semanticscholar.org/paper/7551d2b7ca961dd3d6f1e79086321b021411941d
  • DOI: 10.1155/2022/6638244
  • PMID: 35222801
  • PMCID: 8881136
  • Citations: 29
  • Summary: The data identified NR4A1 as a novel regulator of LPS‐related acute lung injury through regulation of mitochondrial fusion and necroptosis, indicating therapeutic promises of targeting NR4A1 in the treatment of acute lung injury in clinical practice.
  • Evidence snippets:
  • Snippet 1 (score: 0.440) > Acute respiratory distress syndrome (ARDS), a diffused injury of the lung parenchyma evoked by pathological stresses including severe infection, anoxia, ischemia, trauma, and surgery [1,2], is deemed one of the most common refractory complications with high mortality and mortality in critically ill patients [3,4]. To date, effective therapy for ARDS is still lacking. Ample experimental findings have unveiled the pathogenesis of ARDS with beneficial effects from pharmacological and mechanical conditioning strategies [5]. In particular, a number of mechanisms have been Oxidative Medicine and Cellular Longevity suggested to contribute to ARDS including oxidative stress, inflammation response, and immunomodulatory disorders [6][7][8]. A better understanding of the interplay among these pathological factors should help to unveil novel therapeutic strategies for acute lung injury and clinical outcomes in patients with ARDS. > Given the important role of mitochondria in energy metabolism through consumption of nutrient and oxygen by way of tricarboxylic acid cycle and oxidative phosphorylation (OXPHOS), mitochondria serve as the powerhouse in cells [9]. Besides, a range of cellular physiological processes such as oxidative stress, calcium regulation, signaling transduction, cell movement, growth, proliferation, and death are controlled by mitochondria, especially in respiratory diseases including but not limited to ARDS. Mitochondrialderived reactive oxygen species (ROS) has aroused considerable attention due to its dual regulatory role in ARDS [10]. In lipopolysaccharide-(LPS-) induced acute lung injury, mitochondrial APT production is reduced whereas levels of ROS are elevated, because of neutrophil accumulation in lung tissues [11]. Furthermore, mitochondrial ROStriggered oxidative damage as well as mitochondrial apopto-sis is noted in kidney tissues following LPS challenge [12]. Another independent study in a model of endotoxininduced ARDS revealed a connection between mitochondrial bioenergetic dysfunction and impaired pulmonary ventilation [13]. These findings indicate a role of mitochondrial dysfunction in acute lung injury although precise molecular mechanisms are not fully understood.

[11] Candidate genes and pathogenesis investigation for sepsis-related acute respiratory distress syndrome based on gene expression profile

  • Authors: Min Wang, Jingjun Yan, Xingxing He, Q. Zhong, Cheng-ye Zhan et al.
  • Year: 2016
  • Venue: Biological Research
  • URL: https://www.semanticscholar.org/paper/88c3aefab1fe6d50848633dff472cda669b57ae2
  • DOI: 10.1186/s40659-016-0085-4
  • PMID: 27090785
  • PMCID: 4835843
  • Citations: 22
  • Influential citations: 1
  • Summary: Genes including CCNB1, CCNB2 and TOP2A, as well as transcription factors like FOXM1 might be used as the novel gene therapy targets for sepsis related ARDS.
  • Evidence snippets:
  • Snippet 1 (score: 0.439) > Acute respiratory distress syndrome (ARDS) is a potentially devastating form of acute inflammatory lung injury as well as a major cause of acute respiratory failure. Although researchers have made significant progresses in elucidating the pathophysiology of this complex syndrome over the years, the absence of a universal detail disease mechanism up until now has led to a series of practical problems for a definitive treatment. This study aimed to predict some genes or pathways associated with sepsis-related ARDS based on a public microarray dataset and to further explore the molecular mechanism of ARDS. A total of 122 up-regulated DEGs and 91 down-regulated differentially expressed genes (DEGs) were obtained. The up- and down-regulated DEGs were mainly involved in functions like mitotic cell cycle and pathway like cell cycle. Protein–protein interaction network of ARDS analysis revealed 20 hub genes including cyclin B1 (CCNB1), cyclin B2 (CCNB2) and topoisomerase II alpha (TOP2A). A total of seven transcription factors including forkhead box protein M1 (FOXM1) and 30 target genes were revealed in the transcription factor-target gene regulation network. Furthermore, co-cited genes including CCNB2-CCNB1 were revealed in literature mining for the relations ARDS related genes. Pathways like mitotic cell cycle were closed related with the development of ARDS. Genes including CCNB1, CCNB2 and TOP2A, as well as transcription factors like FOXM1 might be used as the novel gene therapy targets for sepsis related ARDS.

[12] A comprehensive systematic review of the phenotypes and their role in improving medications and clinical results in the acute respiratory distress syndrome: exploring the potential of personalized therapy

  • Authors: E. R. Surabhi, Devanshu J. Patel, Asha Kademane, Pradeep Nirala
  • Year: 2024
  • Venue: Multidisciplinary Reviews
  • URL: https://www.semanticscholar.org/paper/82200075790bb220d807d97ca7f9f49d62449341
  • DOI: 10.31893/multirev.2023ss006
  • Summary: The significance of customizing research trials to the exact stage of lung damage that patients are experiencing, as well as premature treatment and preventive intervention and developed ARDS therapy are discussed.
  • Evidence snippets:
  • Snippet 1 (score: 0.438) > The Acute Respiratory Distress Syndrome (ARDS) is a disorder that can be severe and it is characterized by severe breathing difficulties, such as the various clinical risk factors, lung injury mechanisms, microbiological aspects and biological factors. The current systematic review intends to investigate the phenotypic diversity in ARDS and the possibility of individualized treatment in improving clinical outcomes. In the field of molecular phenotyping, biomarker panels show promise as useful tools for identifying patients who are at risk of developing ARDS, diagnosing the disease, assisting in risk assessment and allowing for ongoing observation. The hyper-inflammatory subphenotype is associated with diseases including metabolic acidosis, shock and worse clinical outcomes. Biologic phenotypes are taken into consideration, such as gene expression, common causal microbiologic infections and plasma protein biomarkers. This review underlines the variations in etiology, clinical manifestations and treatment responses for the diverse phenotypes, including subtypes of direct and indirect lung damage. We will talk about the significance of customizing research trials to the exact stage of lung damage that patients are experiencing, as well as premature treatment and preventive intervention and developed ARDS therapy. Customized therapy can become a reality as a result of improved clinical trial design and execution brought by a deeper comprehension of the interactions between various factors in ARDS.

[13] Single-cell analysis reveals dysregulated inflammatory response in peripheral blood immunity in patients with acute respiratory distress syndrome

  • Authors: Jingjia Mo, Yanli Yang, Jihua Feng, Yanhua Lei, Suhong Huang et al.
  • Year: 2023
  • Venue: Frontiers in Cell and Developmental Biology
  • URL: https://www.semanticscholar.org/paper/38d0e7e914d64151dc384d2d068b30f351473825
  • DOI: 10.3389/fcell.2023.1199122
  • PMID: 37283946
  • PMCID: 10239863
  • Citations: 7
  • Summary: The composition of cells involved in the main peripheral circulation differs in patients with ARDS with different etiologies, and a significant enhancement of the oxidative stress response was observed in the neutrophil subpopulation.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > Introduction: Acute respiratory distress syndrome (ARDS) remains a major clinical challenge for patients in intensive care units. Determining the differential mechanisms underlying ARDS with different etiologies is a key goal to improve the effectiveness of ARDS therapy. Despite growing evidence that different immune cell types are involved in ARDS, the role of altered immune cell subpopulations in disease progression is unelucidated. Methods: In this study, we combined scRNA-seq and bulk-level sequencing to analyze the transcriptomes of peripheral blood mononuclear cells from healthy volunteers and patients with septic ARDS (sep-ARDS) and pneumonic ARDS (PNE-ARDS). Results: Our data revealed differential alterations at the cellular and molecular levels and within biological signaling pathways in ARDS with different etiologies. The dynamics of neutrophils, macrophages (Macs), classical dendritic cells (cDCs), myeloid-derived suppressive cells (MDSCs), and CD8+ T cells varied significantly among groups of different samples, with neutrophils and cDCs at higher, and Macs at significantly lower, amounts in the patients with sep-ARDS. Furthermore, MDSCs were highly enriched only in the sep-ARDS patients, whereas a higher abundance of CD8+ T cells was observed in patients with PNE-ARDS. In addition, these cell subpopulations were found to be significantly involved in apoptosis, inflammatory, and immune-related pathways. In particular, a significant enhancement of the oxidative stress response was observed in the neutrophil subpopulation. Conclusion: Our study shows that the composition of cells involved in the main peripheral circulation differs in patients with ARDS with different etiologies. Studying the role and mechanism of action of these cells during ARDS will provide new opportunities for the treatment of this condition.

[14] Advancement in Precision Medicine and Recommendation System for Clinical Trials Using Deep Learning Methods

  • Authors: A.P.Ponselvakumar, S. Anandamurugan, K.Logeswaran, S.Nivashini, S.K.Showentharya et al.
  • Year: 2021
  • Venue: IOP Conference Series: Materials Science and Engineering
  • URL: https://www.semanticscholar.org/paper/09c40cae147b54bbb86db9825a1c96299acedbc5
  • DOI: 10.1088/1757-899X/1055/1/012110
  • Citations: 6
  • Influential citations: 1
  • Summary: Both combination of recommendation system along with deep learning quality of precision healthcare achieved to patients are revealed.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > The following paper [25] briefly talks about biomarkers which play a significant role within the treatment of respiratory functionalities. It is stated that over 10% of patients hospitalized in critical care are affected by Acute Lung Injury. The most intense type of ALI is Acute respiratory distress syndrome (ARDS) in which 40% fatality rate is observed. The contribution of biomarkers to the pathophysiology of ARDS is considerably very less. Nevertheless, a major problem is that ARDS is such a diverse, multi-factorial, termination condition that the techniques for "lumping and splitting" are severe. > However, the appliance of network biology to ARDS is made possible with the help of human genome sequencing and the provision of improved techniques for the analysis purpose of transcription to mRNA (gene expression), and also due to the development of sensitive immunoassays. In the field of molecular phenotypic is to identify the patients who at the danger to develop ARDS, biomarker panels have gained prospective applications. This composite disease continues to be serious and deadly event even though the process of dealing and controlling of ARDS has been developed. Monoclonal antibodies (anti-TNF) and TNFR fusion protein have given uncompromising results. However, with the advancement in the techniques of mechanical ventilation, a neuromuscular blocker has shown some positive result, and somatic cell therapy is being well developed. In the future, it is expected that this could give logical remedial targets, and eventually improve clinical care since the comprehension role of biomarkers are incorporated into the pathophysiology of ARDS and lung problems. > This paper [26] briefly discusses the approach that though there are many clinical benefits specifying the importance to produce treatment for sparse diseases and cancer but the impact on the dealing and control of quite composite diseases, like type 2 diabetes, remains too low. This paper primarily specifies the ways by which people fall as a prey to poor health through the appliance of diagnostic labels. This review suggests a different, 'palette' model, center placed on a molecular taxonomy that aims on positioning an individual in accordance to the most pathophysiological processes that put-up to the risk and development of diabetes.

[15] Longitudinal multi-omic signatures of ARDS and sepsis inflammatory phenotypes identify key pathways associated with mortality

  • Authors: N. Alipanah-Lechner, L. Neyton, Pratik Sinha, Carolyn Leroux, K. Bardillon et al.
  • Year: 2025
  • Venue: medRxiv
  • URL: https://www.semanticscholar.org/paper/7ac6ad9892581d7caf0f6dd0c6c799180f575391
  • DOI: 10.1101/2025.05.07.25327117
  • PMID: 40963763
  • PMCID: 12440049
  • Citations: 3
  • Summary: Analysis of blood samples from ARDS patients in the ROSE trial revealed metabolomic and transcriptomic differences between Hyperinflammatory and Hypoinflammatory phenotypes and suggest potential therapeutic targets for precise treatment strategies in critical illness.
  • Evidence snippets:
  • Snippet 1 (score: 0.432) > The acute respiratory distress syndrome (ARDS) and sepsis are devastating critical illness syndromes with unacceptably high mortality rates approaching 40-50% in the United States (1,2). A significant challenge to developing effective treatments has been the marked heterogeneity in clinical presentation, underlying biology, and treatment responses among affected patients (3,4). > Recent advances in molecular phenotyping have identified reproducible subgroups of ARDS and sepsis patients with distinct pathobiology. Latent class analyses (LCA) of clinical and plasma protein data consistently reveal two predominant phenotypes: a "Hyperinflammatory" phenotype characterized by elevated plasma inflammatory protein biomarkers, shock, and higher mortality, and a "Hypoinflammatory" phenotype with relatively lower inflammatory protein biomarkers and better outcomes (5)(6)(7)(8)(9)(10). These phenotypes, identified across multiple ARDS and sepsis cohorts, demonstrate differential therapeutic responses in secondary analyses of randomized trials, suggesting they represent endotypes with distinct disease mechanisms (5,11,12). Clinical trials incorporating prospective phenotyping are being developed, including the PANTHER trial, which will start enrolling in mid-2025 (13). However, the biological processes driving each phenotype and mechanisms underlying unfavorable outcomes within each phenotype remain poorly understood. While protein biomarker studies have provided valuable insights into inflammatory patterns, they capture only a small fraction of the complex molecular landscape. > Previous metabolic profiling of 93 patients with ARDS demonstrated that the Hyperinflammatory phenotype exhibits reduced circulating lipids and a glycolytic shift, while transcriptomic analyses revealed increased expression of genes related to the innate immune response and tissue remodeling and reduced interferon signaling (10,14). However, isolatedomic approaches may miss critical interactions between cellular programming and systemic metabolism essential for understanding disease processes and treatment responses. > In this study, we applied longitudinal multi-omics profiling to characterize the molecular basis of ARDS/sepsis inflammatory phenotypes and identify mechanisms associated with poor outcomes.

[16] Development and functional significance of the pulmonary surfactant system

  • Authors: R. Shakhbanov, M. N. Asadulaeva, S.N. Alieva, A.A. Alimkhanova
  • Year: 2021
  • Venue: RUDN Journal of Medicine
  • URL: https://www.semanticscholar.org/paper/659ee76d2589b60002a27426d73bbf9734de6c63
  • DOI: 10.22363/2313-0245-2021-25-4-321-331
  • Citations: 2
  • Summary: To increase the effectiveness of pharmacological and respiratory therapy of acute respiratory distress syndrome, as well as to identify the role of the surfactant system of the lungs in the onset of inflammation against the background of tuberculosis and the development of regeneration mechanisms that affect the course and outcome of the disease.
  • Evidence snippets:
  • Snippet 1 (score: 0.429) > Relevance. Prevention of the development of postoperative acute respiratory distress syndrome during operations on the descending thoracic aorta increases the effectiveness of therapy. The study of damage to the surfactant complex during ischemia and reperfusion of the lungs is relevant, since it involves the prophylactic use of the surfactant preparation during operations on the descending part of the thoracic aorta, which are characterized by a high risk of postoperative acute respiratory distress syndrome. Objective: to increase the effectiveness of pharmacological and respiratory therapy of acute respiratory distress syndrome, as well as to identify the role of the surfactant system of the lungs in the onset of inflammation against the background of tuberculosis and the development of regeneration mechanisms that affect the course and outcome of the disease. Materials and Methods. The study involved 24 people, including 14 volunteer patients with a diagnosed respiratory disease in an acute course (while the whole group received the drug from the study as an additional therapy). The sample of 14 people was formed solely due to the compliance of these patients with the criteria that were established before the start of the study of the drug, which had postoperative acute respiratory distress syndrome of various origins in their diagnosis. Results and Discussion. For a comprehensive laboratory determination, an algorithm was used that corresponded to the state standard to identify postoperative acute respiratory distress syndrome. For each participant in the experiments, it was proposed to develop a plan of treatment procedures, taking into account individualization and standardization. Conclusion. Some of the resulting data are collected with respect to the surfactant pulmonary system, which is presented in a compactor model format. A number of basic components are reflected here, which are classified according to cellular and non-cellular factors. At the same time, the surfactant substance helps to reduce the pronounced swelling, which can significantly reduce the process of sticking of the alveolar structures during inhalation. All this added up to the normal system of gas metabolism in the lung structures, including the control of the mucociliary system, which acts as a natural stimulator of the function of alveolar macrophages.

[17] Values of integration between lipidomics and clinical phenomes in patients with acute lung infection, pulmonary embolism, or acute exacerbation of chronic pulmonary diseases: a preliminary study

  • Authors: Danyan Gao, Linlin Zhang, Dongli Song, Jiapei Lv, Linyan Wang et al.
  • Year: 2019
  • Venue: Journal of Translational Medicine
  • URL: https://www.semanticscholar.org/paper/bfd5c241ee1900a466476b56326304c9c9e0d73a
  • DOI: 10.1186/s12967-019-1898-z
  • PMID: 31109325
  • PMCID: 6528323
  • Citations: 22
  • Summary: It is demonstrated that lipidomic profiles of patients with acute lung diseases are different from healthy lungs, and there are also disease-specific portions of lipidomics among SAP, APE, or AECOPD.
  • Evidence snippets:
  • Snippet 1 (score: 0.428) > Acute lung injury is a major challenge and cause of patient morbidity and mortality in pulmonary critical care units, as an early stage of acute respiratory distress syndrome (ARDS), although molecular diagnosis and therapy are still lacking due to the complex pathogenesis, severity, and systemic responses [1]. Acute infection is one of common factors that can induce the exacerbation of chronic lung diseases. Chen et al., initially identified disease-specific dynamic biomarkers for severe pneumonia or severe pneumonia-associated-ARDS by integrating proteomic profiles of inflammatory mediators with clinical informatics as part of clinical bioinformatics [2]. They found that specific protein-based biomarkers comparing diseased tissue with healthy tissue and diseased tissue and diseased tissue had a significant correlation with clinical phenomes measured by Digital Evaluation Score System (DESS) scores. Shi et al. identified specific immunomodulatory mediators by evaluating dynamic genomic and proteomic profiles of peripheral blood mononuclear cells and plasma in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and found a complex network of AECOPD-or COPD-specific immunomodulatory mediators [3]. In addition to changes of genomic and proteomic profiles, alterations of systemic metabolisms are also another important factor which can influence disease severity, duration, progression, and patient response to therapy, although the metabolism has been ignored in understanding of molecular mechanisms in the development of acute and chronic pulmonary diseases. > Clinical lipidomics is a new integrative approach to identify the disease-specific correlation and regulation between a large scale of lipid elements measured in liquid biopsies from patients with their clinical phenomes [4]. Clinical lipidomics has been suggested as a novel approach in discovering new categories of disease-specific biomarkers or therapeutic targets and could play a key role in improving our understanding of molecular mechanisms in disease metabolisms [5]. However, challenges still remain to be faced and overcome in prior to clinical practice [6].

[18] Enhanced mortality prediction in pneumonia-associated acute respiratory distress syndrome: a model integrating lymphocyte subsets with clinical parameters in non-immunosuppressed adults

  • Authors: Z. Xing, Hua Guo, Ting Ao, Jin-Xiang Wang, Ming Hu
  • Year: 2026
  • Venue: Frontiers in Medicine
  • URL: https://www.semanticscholar.org/paper/c51c13a1a85020abf45c9c16509242a87294f662
  • DOI: 10.3389/fmed.2026.1844614
  • PMID: 42245930
  • PMCID: 13230041
  • Summary: A multidimensional model for predicting in-hospital mortality in non-immunosuppressed adult patients with pneumonia-associated ARDS was developed and demonstrated excellent predictive performance, which was significantly higher than that of the baseline model.
  • Evidence snippets:
  • Snippet 1 (score: 0.426) > Acute respiratory distress syndrome (ARDS) is a critical clinical syndrome characterized by diffuse pulmonary inflammation and damage to the alveolar epithelial-capillary barrier. The clinical, physiological, biological and imaging manifestations of ARDS are highly heterogeneous. It is primarily be divided into two types: intrapulmonary and extrapulmonary. The condition manifests as progressive respiratory distress and refractory hypoxemia (1)(2)(3). Despite substantial advancements in mechanical ventilation strategies and supportive care in recent years, ARDS continues to be a relatively frequent condition associated with high morbidity and mortality, with severe ARDS cases exhibiting mortality rates as high as 46-66% (4-7). Pneumonia constitutes a major etiological factor for ARDS, accounting for approximately 59% of all ARDS cases (5). In patients with pneumoniaassociated acute respiratory distress syndrome (p-ARDS), the interplay between the initial pathogen invasion and the dysregulated host immune response serves as a critical determinant of clinical progression and prognosis. > The Sequential Organ Failure Assessment (SOFA) score and the CURB-65 score are clinically established tools for quantifying the extent of organ dysfunction and predicting mortality in pneumonia patients. These tools primarily serve to assess the extent of physiological dysfunction but demonstrate significant limitations in evaluating underlying pathophysiological mechanisms, particularly the immune status. In studies of COVID-19-related ARDS, immune dysregulation has been identified as a core feature of the disease pathophysiology, typically manifesting as significant lymphopenia and alterations in the distribution and function of key lymphocyte subsets, such as helper T cells (8). Meanwhile, pertinent studies have confirmed that adaptive immune impairment occurs during sepsis. The increased apoptosis of T cells, B cells, and dendritic cells drives a shift in the immune system from an initial pro-inflammatory state toward an anti-inflammatory and immunosuppressive response, potentially resulting in immunosuppression (9).

[19] [Genetic predisposition and Pediatric Acute Respiratory Distress Syndrome: New tools for genetic study].

  • Authors: B. Erranz, Jan Wilhelm, Raquel Riquelme, Pablo Cruces
  • Year: 2015
  • Venue: Revista chilena de pediatria
  • URL: https://www.semanticscholar.org/paper/9a0026c01cee098398beff7678483ecb888e06ce
  • DOI: 10.1016/j.rchipe.2015.04.016
  • PMID: 26235685
  • Summary: Genome-wide association studies can objectively examine variations of genes involved in key processes of tissue, cellular and molecular lung damage to help identify important new genes and pathogenetic pathways for future analysis and have diagnostic and therapeutic implications.
  • Evidence snippets:
  • Snippet 1 (score: 0.425) > Acute respiratory distress syndrome (ARDS) is the most severe form of respiratory failure. Theoretically, any acute lung condition can lead to ARDS, but only a small percentage of individuals actually develop the disease. On this basis, genetic factors have been implicated in the risk of developing ARDS. Based on the pathophysiology of this disease, many candidate genes have been evaluated as potential modifiers in patient, as well as in animal models, of ARDS. Recent experimental data and clinical studies suggest that variations of genes involved in key processes of tissue, cellular and molecular lung damage may influence susceptibility and prognosis of ARDS. However, the pathogenesis of pediatric ARDS is complex, and therefore, it can be expected that many genes might contribute. Genetic variations such as single nucleotide polymorphisms and copy-number variations are likely associated with susceptibility to ARDS in children with primary lung injury. Genome-wide association (GWA) studies can objectively examine these variations, and help identify important new genes and pathogenetic pathways for future analysis. This approach might also have diagnostic and therapeutic implications, such as predicting patient risk or developing a personalized therapeutic approach to this serious syndrome.

[20] Comorbidity Networks in Cardiovascular Diseases

  • Authors: Héctor A. Cruz-Ávila, M. Vallejo, M. Martínez-García, E. Hernández-Lemus
  • Year: 2020
  • Venue: Frontiers in Physiology
  • URL: https://www.semanticscholar.org/paper/1454c6cc3ca61441b24fd8c65ce02935b2845274
  • DOI: 10.3389/fphys.2020.01009
  • PMID: 32982776
  • PMCID: 7485389
  • Citations: 35
  • Influential citations: 1
  • Summary: It is found that comorbidity networks are highly centralized in prevalent diseases, such as cardiac arrhythmias, heart failure, chronic kidney disease, hypertension, and ischemic diseases, which may lead to further development of better, integrated therapeutic strategies.
  • Evidence snippets:
  • Snippet 1 (score: 0.424) > The first one of such pairs is formed by Other and unspecified encephalopathy (G93.4) and Acute respiratory distress syndrome (J80.X) with 437 common genes (JI = 0.827651515). These apparently disparate diseases share physiological and clinical associations. Burad et al. (2012) found that acute respiratory syndrome in pneumonia patients leads to strong systemic ischemia that may in turn develop into acute encephalopathy. This finding has been further confirmed in a very large (5.6 million cases) epidemiological risk factor study of the group of Bell in the US (Rincon et al., 2014). Aside from environmental and other risk factors, these diseases large number of shared genes are involved in a number of relevant biomolecular pathways, ranging from essential metabolism (folate-mediated one-carbon metabolism, antifolate resistance), signal transduction (cell adhesion, transendothelial leukocyte migration, a tight junction regulation). Also, including immune response and inflammation (response to hepatitis C, natural killer cell-mediated cytotoxicity, response to measles, Alzheimer's disease, and response to Influenza), as it was evidenced by gene enrichment analysis whose statistical significance was assessed via hypergeometric tests with false discovery rate multiple-testing correction (see Methods). > Closely related to this pair is the second one formed by Other and unspecified encephalopathy (G93.4) and Acute respiratory failure (J96.0) with 440 common genes representing a JI = 0.787119857, these genes refer to similar pathways involved with the addition of statistical enrichment of the protein digestion and absorption pathway. Understanding the role that such molecular processes may have in the onset and progression of both diseases, of the comorbidity and of their potential multimorbidity relations in the context of the CVCnetwork (see Figure 4), may prove useful, particularly in the design of combined therapeutic strategies with special emphasis in the critically ill patients in intensive care units. > In this regard, we may mention the following: it is known that the physiological manifestation of such biomolecular process starts in the microvascular endothelium (MVE).

Notes

  • This provider combines search_papers_by_relevance with snippet_search.
  • No synthesis or second-stage model call is performed.