Conserved Fibrotic Response Module

Module fibrotic_response 44 disorders Pathograph 6

A conserved pathological module representing the dysregulation of normal wound healing (GO:0042060) that underlies organ fibrosis across tissues. Tissue injury triggers inflammation and resident mesenchymal cell activation, leading to myofibroblast transdifferentiation, excessive extracellular matrix deposition, and progressive architectural distortion with organ dysfunction. This module captures the shared core of fibrotic disease across liver, lung, heart, kidney, intestine, skin, and other organs, though the extent of that sharing below the core chain is organ-dependent -- see the `interp_fibrotic_chain_organ_divergence` discussion. Individual disorder entries declare conformance via conforms_to on their pathophysiology nodes, substituting organ-specific cell types and anatomical locations while preserving the conserved causal chain and signaling axes.

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Pathophysiology Nodes

5 shared nodes are defined in this module.

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Cell Types

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Biological Processes

Wound Healing GO:0042060 ↕ DYSREGULATED Inflammatory Response GO:0006954 ↑ INCREASED Leukocyte Migration GO:0050900 ↑ INCREASED TGF-beta Receptor Signaling GO:0007179 ↑ INCREASED ECM Organization GO:0030198 ↑ INCREASED Collagen Biosynthesis GO:0032964 ↑ INCREASED Collagen Fibril Organization GO:0030199 ↑ INCREASED

Notes

This is a mechanism module, not a specific disease. Disorder entries reference individual nodes via conforms_to (e.g., "fibrotic_response#Mesenchymal Cell Activation"). The module defines the expected pathophysiology structure; conforming nodes in disorder files should include the corresponding cell types, biological processes, and causal edges, specialized to their organ context. Key organ-specific substitutions: liver uses hepatic stellate cells (CL:0000632), lung uses pulmonary fibroblasts, heart uses cardiac fibroblasts, kidney uses mesangial cells (CL:0000650) or pericytes.

Discussions and Knowledge Gaps

How far below the core chain does this module's conserved-fibrosis claim hold, given that the TGF-beta arms engaged, the baseline ECM programme, and the response to a core-pathway inhibitor all differ by organ?

INTERPRETATION OPEN interp_fibrotic_chain_organ_divergence

Attached to: Mesenchymal Cell Activation Excessive ECM Deposition Scar-in-a-Jar macromolecular-crowding fibroblast fibrosis assay

Murine and human precision-cut tissue slice (PCTS) studies from the same group test this module's conserved-chain claim directly, across small intestine, liver and kidney (murine) and liver, kidney and gut (murine and human), and find it holds only partway. The precursor lineage and activation programme are conserved: a cross-species single-cell atlas finds two universal fibroblast transcriptional subtypes shared between mouse and human tissues, so substituting the organ-specific mesenchymal cell type on this module's Mesenchymal Cell Activation node remains a safe, well-supported move. Below that level, three things diverge by organ. First, at baseline, 70% of ECM-related genes are differentially expressed across organs, which bounds the Excessive ECM Deposition node's claim that matrix composition merely "may vary" by organ. Second, TGF-beta signalling itself is not uniform: canonical and non-canonical arms are both engaged in liver and kidney PCTS, but only the canonical, Smad-dependent arm is engaged in intestinal PCTS. Separately, a human ex vivo liver study shows galunisertib inhibits ALK5-mediated Smad2 phosphorylation without affecting BMP-Smad1 signalling -- a finding about the drug's mechanism of action, not additional evidence for the canonical/non-canonical split, since SMAD1 is a BMP-Smad effector rather than a non-canonical (non-Smad) TGF-beta mediator. Third, a drug aimed squarely at that shared TGF-beta receptor node, galunisertib, produces organ-specific rather than uniform responses in murine PCTS -- so this module's one experimental model, a TGF-beta-1-driven fibroblast monoculture read out on matrix deposition, cannot be assumed to predict organ-specific drug response even though it exercises a genuinely conserved node. None of this is a translational, mouse-versus-human question: a companion study of culture-associated transcriptional change in murine and human PCTS reaches the same conserved-core/organ-specific-detail pattern independently, in human liver, kidney and gut tissue. Intestine is the organ where the divergence is sharpest, and it is also the one organ this module's own description did not name before this edit (it listed "liver, lung, heart, kidney, skin, and other organs"). There is currently no intestinal conformer to this module on `main` -- `Crohn_Disease` has a fibrosis node with `fibroblast` and `myofibroblast cell` types and stricture phenotypes but does not declare `conforms_to` against this module. So the practical consequence of this discussion is prospective rather than corrective: a future intestinal conformer should not assume the non-canonical TGF-beta arm applies, and should expect the baseline ECM programme and the response to a TGF-beta-pathway inhibitor to need organ-specific evidence rather than inheriting this module's liver/lung/kidney-derived citations.

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Experimental Models

Scar-in-a-Jar macromolecular-crowding fibroblast fibrosis assay PRIMARY_CELL_CULTURE namo:TwoDCellCulture

A macromolecular-crowding culture system in which an inert crowder added to the medium excludes volume and thereby accelerates procollagen processing and extracellular deposition, producing a quantifiable collagen matrix in days rather than weeks. TGF-beta 1 is supplied to drive the fibroblast to myofibroblast transition, and the deposited matrix is read directly in the well by immunofluorescence or, in the prolonged variant, by neoepitope ELISAs on the supernatant. The collagen-producing cell type is a parameter of the assay rather than a fixed feature of it, which is what makes this a module-level rather than an organ-level model. The same platform has been run with embryonic and adult lung fibroblasts, embryonic and adult dermal fibroblasts, corneal keratocytes and vocal fold fibroblasts, so the two nodes it is linked to here are exercised without committing to an organ.

Organism

human NCBITaxon:9606

Cell source

Primary human fibroblasts, with the organ of origin chosen per experiment - adult dermal fibroblasts in the crowder-comparison study and primary lung fibroblasts from healthy donors in the prolonged variant. Earlier work used the WI-38 embryonic lung fibroblast line.

Culture

Two-dimensional fibroblast monoculture in medium containing a macromolecular crowder and ascorbate, with recombinant TGF-beta 1 as the pro-fibrotic stimulus. Read out by in-well immunofluorescence of deposited collagen and alpha-smooth muscle actin, or over 12 days by extracellular matrix neoepitope ELISAs on the culture supernatant.

Publication

PMID:34028741

Pathograph links

Mesenchymal Cell Activation recapitulates fidelity: moderate Recombinant TGF-beta 1 drives resident fibroblasts through the defining transition of this node - conversion to an alpha-smooth-muscle-actin positive myofibroblast - and the conversion is measured directly by alpha-SMA staining or ELISA rather than inferred from downstream matrix.

Limitations: Fibroblast monoculture. TGF-beta 1 is supplied exogenously in place of the endogenous injury-driven latent-TGF-beta activation route, so the upstream epithelial injury and inflammatory amplification steps of this module are bypassed rather than modeled. Alpha-SMA induction is slower than matrix output in the prolonged variant, where it does not separate from control until day 8, so a short assay can register matrix deposition while the activation marker is still flat.

Readouts

alpha-smooth muscle actin expression

Direction: INCREASED

Interpretation: Alpha-SMA is the canonical marker of fibroblast to myofibroblast conversion. Measured here as a protein ELISA on culture supernatant, it is the direct protein-level readout of this node.

Evidence: 2

ACTA2 (alpha-SMA) transcript expression in dermal fibroblasts

Direction: INCREASED

Interpretation: Transcript-level induction of the myofibroblast marker gene shows the same activation endpoint reached in dermal rather than lung fibroblasts, establishing that the node is exercised outside one organ.

Evidence: 1

Excessive ECM Deposition recapitulates fidelity: moderate The point of the crowding step is to make deposited matrix the net read-out. Activated fibroblasts lay down a collagen matrix that is quantified in the well, and in the prolonged variant type I, III and VI collagen formation and fibronectin deposition are measured separately.

Limitations: The deposited matrix is a two-dimensional in-well layer, not three-dimensional tissue architecture, so matrix stiffening, cross-linked fibril remodeling and the mechanical feedback onto the fibroblast are not represented. Deposition is accelerated by an artificial crowder rather than occurring at tissue rates. The degradation arm is only partly covered: collagenolytic enzyme transcripts (MMP1, CTSK) are measured and fall, but TIMP-mediated blockade of matrix turnover is not measured, and no readout captures net matrix turnover directly.

Readouts

Type I and type VI collagen formation (PRO-C1, PRO-C6)

Collagen Biosynthesis GO:0032964

Direction: INCREASED

Interpretation: Elevated collagen formation biomarkers are the direct measurement of the excessive matrix production this node names.

Evidence: 2

Fibronectin deposition (FBN-C)

ECM Organization GO:0030198

Direction: INCREASED

Interpretation: Fibronectin rises alongside collagen under TGF-beta 1, showing the node is exercised beyond a single matrix protein.

Evidence: 1

Collagen-degrading enzyme transcripts (MMP1, CTSK)

ECM Organization GO:0030198

Direction: DECREASED

Interpretation: MMP1 and CTSK fall under TGF-beta 1 while the matrix genes rise, so the system reproduces part of the production-versus-degradation imbalance the node names rather than production alone.

Evidence: 1

Findings

The collagen-producing cell in this assay is a parameter rather than a fixed organ-specific feature, and the platform has been run across lung, dermal, corneal and vocal fold fibroblasts, which is what licenses it as a model of the module rather than of one organ's fibrosis.

Evidence: 2

Macromolecular crowding is what compresses fibrotic matrix deposition into a timescale short enough to screen against, which is the practical reason this system rather than a conventional fibroblast culture is the module's exemplar.

Evidence: 1

tissue_term is deliberately omitted. The assay has no tissue of its own: the fibroblast source is a parameter, and binding any one organ would assert a specificity the platform does not have. This is the property that licenses a module-level model here rather than the organ-specific lung chip and liver microtissue plate that prompted the gap (issue #9997).

Evidence: 1

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Used By Disorder Entries

Adenomyosis via Lesional Fibrosis and Myofibroblast Transdifferentiation → Mesenchymal Cell Activation

Alcohol-Associated Liver Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic Extracellular Matrix Deposition → Excessive ECM Deposition , Cirrhotic Architectural Distortion and Functional Failure → Architectural Distortion and Organ Dysfunction

Alpha-1 Antitrypsin Deficiency via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation

Asbestosis via Biopersistent asbestos fiber deposition → Tissue Injury , Chronic sterile alveolitis → Inflammatory Recruitment and Amplification , Myofibroblast differentiation → Mesenchymal Cell Activation , Excessive extracellular matrix deposition → Excessive ECM Deposition , Interstitial fibrosis and architectural distortion → Architectural Distortion and Organ Dysfunction

Asherman_Syndrome via Endometrial Basal Layer Injury → Tissue Injury , Stromal Fibrogenic Activation → Mesenchymal Cell Activation , Excessive Endometrial Matrix Deposition → Excessive ECM Deposition , Intrauterine Adhesion Formation → Architectural Distortion and Organ Dysfunction

Biliary Atresia via Portal Mesenchymal Cell Activation → Mesenchymal Cell Activation , Fibro-obliteration of the Biliary Tree → Excessive ECM Deposition

Budd-Chiari Syndrome via Congestive Hepatic Fibrosis → Mesenchymal Cell Activation

CAPN5-Related Vitreoretinopathy via Fibrotic Proliferative Vitreoretinopathy and Progressive Blindness → Architectural Distortion and Organ Dysfunction

Caroli disease via Progressive Peribiliary Fibrosis → Excessive ECM Deposition

Chagas disease via Myocardial fibrosis and arrhythmogenic substrate → Excessive ECM Deposition

Coal Workers Pneumoconiosis via Alveolar and Small-Airway Tissue Injury → Tissue Injury , Sustained Inflammatory Cell Recruitment and Amplification → Inflammatory Recruitment and Amplification , Fibroblast Activation and Myofibroblast Differentiation → Mesenchymal Cell Activation , Peribronchiolar Collagen Deposition and Coal Macule Formation → Excessive ECM Deposition , Nodule Coalescence into Progressive Massive Fibrosis → Architectural Distortion and Organ Dysfunction

Congenital Merosin-deficient Muscular Dystrophy 1A via Endomysial Fibrosis and Replacement of Muscle → Excessive ECM Deposition

Deployment-Related Constrictive Bronchiolitis via Sustained Club Cell Injury in Membranous Bronchioles → Tissue Injury , Peribronchiolar Myeloid and Alveolar Macrophage Accumulation → Inflammatory Recruitment and Amplification , TGF-beta Activation and Myofibroblast Recruitment → Mesenchymal Cell Activation , Peribronchiolar Collagen Deposition → Excessive ECM Deposition , Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles → Architectural Distortion and Organ Dysfunction

Dilated Cardiomyopathy 1P via Myocardial Replacement Fibrosis → Excessive ECM Deposition

Dupuytren Contracture via Fascial Microinjury and Aberrant Wound Healing → Tissue Injury , Profibrotic Signaling and Inflammatory Amplification → Inflammatory Recruitment and Amplification , Myofibroblast Activation and Contraction → Mesenchymal Cell Activation , Excessive Collagen Deposition and Cord Formation → Excessive ECM Deposition , Digital Flexion Contracture and Hand Dysfunction → Architectural Distortion and Organ Dysfunction

Endomyocardial Fibrosis via Chronic antigenic or toxic stimulus in a susceptible host → Tissue Injury , Sustained eosinophilia and Th2-skewed immune activation → Inflammatory Recruitment and Amplification , Fibroblast activation and excessive collagen deposition → Mesenchymal Cell Activation , Dense endocardial fibrous scar → Excessive ECM Deposition , Apical and inflow-tract cavity obliteration → Architectural Distortion and Organ Dysfunction

Eosinophilic Fasciitis via TGF-beta-Driven Fascial Fibroblast Activation → Mesenchymal Cell Activation

Familial Vesicoureteral Reflux via Ascending Infection and Acute Pyelonephritis → Tissue Injury , Renal Inflammatory Cell Recruitment → Inflammatory Recruitment and Amplification , Interstitial Myofibroblast Activation → Mesenchymal Cell Activation , Renal Cortical Scarring → Excessive ECM Deposition , Reflux Nephropathy and Progressive Nephron Loss → Architectural Distortion and Organ Dysfunction

Formaldehyde Poisoning via Fibrotic stricture formation → Architectural Distortion and Organ Dysfunction

Glycogen Storage Disease Type VI via Hepatic Stellate Cell Activation and Fibrogenesis → Mesenchymal Cell Activation

Hepatic Fibrinogen Storage Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic ECM Deposition → Excessive ECM Deposition

Hepatic veno-occlusive disease-immunodeficiency syndrome via Hepatic stellate cell activation and fibrotic remodeling → Mesenchymal Cell Activation , Progressive hepatic fibrosis and organ dysfunction → Excessive ECM Deposition

Hypertrophic Cardiomyopathy 30, Atrial via Cardiac Fibroblast Activation → Mesenchymal Cell Activation , Left Atrial Fibrosis → Excessive ECM Deposition

Idiopathic Hypereosinophilic Syndrome via Granule Protein-Mediated Cytotoxic Tissue Injury → Tissue Injury , Endomyocardial Fibrosis and Restrictive Physiology → Excessive ECM Deposition

Idiopathic Interstitial Pneumonia via Injury to the alveolar-interstitial compartment of unknown cause → Tissue Injury , Myofibroblast activation in the fibrosing entities → Mesenchymal Cell Activation , Progressive pulmonary fibrosis → Architectural Distortion and Organ Dysfunction

Idiopathic Pulmonary Fibrosis via Repetitive alveolar epithelial injury and aberrant repair → Tissue Injury , Profibrotic macrophage recruitment and amplification → Inflammatory Recruitment and Amplification , Fibroblast activation and myofibroblast differentiation → Mesenchymal Cell Activation , Excessive extracellular matrix deposition → Excessive ECM Deposition , Architectural distortion and gas-exchange failure → Architectural Distortion and Organ Dysfunction

IgG4-Related Disease via Storiform Fibrosis → Excessive ECM Deposition , Fibroblast Activation and Collagen Production → Mesenchymal Cell Activation

Liver Cirrhosis via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic ECM Deposition → Excessive ECM Deposition , Cirrhotic Architectural Distortion → Architectural Distortion and Organ Dysfunction

Mitral Valve Prolapse via Regional Left Ventricular Fibrosis → Excessive ECM Deposition

Mucous Membrane Pemphigoid via Profibrotic Conjunctival Fibroblast Activation → Mesenchymal Cell Activation , Mucosal Subepithelial Fibrosis → Excessive ECM Deposition

Paraquat Poisoning via TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium → Mesenchymal Cell Activation , Progressive Pulmonary Fibrosis → Excessive ECM Deposition

Pericarditis via Pericardial injury from a heterogeneous trigger → Tissue Injury , Fibrotic organization of the pericardium → Excessive ECM Deposition

Primary Aldosteronism via Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress → Inflammatory Recruitment and Amplification , Myocardial and Renal Interstitial Fibrosis → Excessive ECM Deposition

Progressive Familial Intrahepatic Cholestasis via Hepatic Stellate Cell Activation and Biliary Fibrosis → Mesenchymal Cell Activation

Proliferative Vitreoretinopathy via RPE Epithelial-Mesenchymal Transition → Mesenchymal Cell Activation

Pulmonary Alveolar Microlithiasis via Interstitial Fibrosis and Restrictive Physiology → Architectural Distortion and Organ Dysfunction

Raine Syndrome via Gingival Fibroblast Activation via TGF-beta and YAP/TAZ → Mesenchymal Cell Activation , Excessive Gingival ECM Deposition and Calcification → Excessive ECM Deposition

Rheumatic Heart Disease via Chronic valve fibrosis, commissural fusion, and calcification → Excessive ECM Deposition

Sarcoidosis via Fibrotic Tissue Remodeling → Mesenchymal Cell Activation

Silicosis via Fibroblast-to-Myofibroblast Activation → Mesenchymal Cell Activation , Excess Collagen Deposition and Silicotic Nodule Formation → Excessive ECM Deposition

Sulfur Mustard Poisoning via Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment → Inflammatory Recruitment and Amplification , TGF-beta Driven Myofibroblast Activation → Mesenchymal Cell Activation , Bronchiolar and Interstitial Collagen Deposition → Excessive ECM Deposition , Bronchiolitis Obliterans and Progressive Airflow Obstruction → Architectural Distortion and Organ Dysfunction

Uterine Leiomyoma via Excessive Extracellular Matrix Deposition and Tissue Stiffening → Excessive ECM Deposition

Volumetric Muscle Loss via Frank Muscle Loss and Destruction of the Regenerative Niche → Tissue Injury , Persistent Open-Wound Inflammatory Stimulus → Inflammatory Recruitment and Amplification , Myofibroblast Activation and Excessive Collagen Deposition → Mesenchymal Cell Activation , Excessive ECM Deposition , Fibrotic Scar Replacement and Persistent Functional Deficit → Architectural Distortion and Organ Dysfunction

Wilson Disease via Hepatic Stellate Cell Activation → Mesenchymal Cell Activation , Excessive Hepatic ECM Deposition → Excessive ECM Deposition

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence-backed metadata.

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Pathophysiology

Tissue Injury

trigger

Chronic or repeated injury to organ-specific parenchymal cells initiates the fibrotic cascade. The nature of injury varies by organ (viral hepatitis in liver, inhaled particles in lung, ischemia in heart, immune complex deposition in kidney) but the downstream response converges on a common inflammatory and reparative program.

Wound Healing GO:0042060 ↕ DYSREGULATED

Used by disorders

Asbestosis as Biopersistent asbestos fiber deposition

Asherman_Syndrome as Endometrial Basal Layer Injury

Coal Workers Pneumoconiosis as Alveolar and Small-Airway Tissue Injury

Deployment-Related Constrictive Bronchiolitis as Sustained Club Cell Injury in Membranous Bronchioles

Dupuytren Contracture as Fascial Microinjury and Aberrant Wound Healing

Endomyocardial Fibrosis as Chronic antigenic or toxic stimulus in a susceptible host

Familial Vesicoureteral Reflux as Ascending Infection and Acute Pyelonephritis

Idiopathic Hypereosinophilic Syndrome as Granule Protein-Mediated Cytotoxic Tissue Injury

Idiopathic Interstitial Pneumonia as Injury to the alveolar-interstitial compartment of unknown cause

Idiopathic Pulmonary Fibrosis as Repetitive alveolar epithelial injury and aberrant repair

Pericarditis as Pericardial injury from a heterogeneous trigger

Volumetric Muscle Loss as Frank Muscle Loss and Destruction of the Regenerative Niche

Downstream

Inflammatory Recruitment and Amplification

Show evidence (1 reference)

PMID:23255577 SUPPORT Other

"Fibrosis is a pathological scarring process that leads to destruction of organ architecture and impairment of organ function. Chronic loss of organ function in most organs, including bone marrow, heart, intestine, kidney, liver, lung, and skin, is associated with fibrosis, contributing to an..."

Establishes that fibrosis is a conserved response to chronic tissue injury across all major organs. Evidence source is OTHER because this is a review synthesizing data from multiple study types.

Inflammatory Recruitment and Amplification

amplifier

Damage-associated molecular patterns (DAMPs) from injured parenchymal cells recruit and activate macrophages, which produce pro-fibrotic cytokines including TGF-beta, PDGF, and IL-13. This inflammatory phase bridges tissue injury to mesenchymal cell activation and is a key amplification step in the fibrotic cascade.

Macrophage CL:0000235

Inflammatory Response GO:0006954 ↑ INCREASED Leukocyte Migration GO:0050900 ↑ INCREASED

Used by disorders

Asbestosis as Chronic sterile alveolitis

Coal Workers Pneumoconiosis as Sustained Inflammatory Cell Recruitment and Amplification

Deployment-Related Constrictive Bronchiolitis as Peribronchiolar Myeloid and Alveolar Macrophage Accumulation

Dupuytren Contracture as Profibrotic Signaling and Inflammatory Amplification

Endomyocardial Fibrosis as Sustained eosinophilia and Th2-skewed immune activation

Familial Vesicoureteral Reflux as Renal Inflammatory Cell Recruitment

Idiopathic Pulmonary Fibrosis as Profibrotic macrophage recruitment and amplification

Primary Aldosteronism as Mineralocorticoid Receptor-Driven Tissue Inflammation and Oxidative Stress

Sulfur Mustard Poisoning as Acute Pro-Inflammatory Cytokine Burst and Neutrophil Recruitment

Volumetric Muscle Loss as Persistent Open-Wound Inflammatory Stimulus

Downstream

Mesenchymal Cell Activation

Show evidence (1 reference)

PMID:21727191 SUPPORT Other

"Platelet aggregation and subsequent degranulation in turn promotes blood vessel dilation and increased permeability, allowing efficient recruitment of inflammatory cells (e.g., neutrophils, macrophages, lymphocytes, and eosinophils) to the site of injury. Neutrophils are the most abundant..."

Directly describes macrophage recruitment and cytokine/chemokine amplification as the inflammatory phase that bridges tissue injury to fibroblast activation. Evidence source is OTHER because this is a review synthesizing human clinical and model organism data.

Mesenchymal Cell Activation

central effector

Resident mesenchymal cells (fibroblasts, hepatic stellate cells, pericytes, or mesangial cells depending on organ) are activated by TGF-beta and other pro-fibrotic signals to transdifferentiate into alpha-SMA-positive myofibroblasts. This is the central effector step of fibrosis, conserved across all organs. The specific precursor cell type varies by tissue but the TGF-beta/Smad signaling axis driving activation is shared.

Fibroblast CL:0000057 Myofibroblast CL:0000186

TGF-beta Receptor Signaling GO:0007179 ↑ INCREASED

Used by disorders

Adenomyosis as Lesional Fibrosis and Myofibroblast Transdifferentiation

Alcohol-Associated Liver Disease as Hepatic Stellate Cell Activation

Alpha-1 Antitrypsin Deficiency as Hepatic Stellate Cell Activation

Asbestosis as Myofibroblast differentiation

Asherman_Syndrome as Stromal Fibrogenic Activation

Biliary Atresia as Portal Mesenchymal Cell Activation

Budd-Chiari Syndrome as Congestive Hepatic Fibrosis

Coal Workers Pneumoconiosis as Fibroblast Activation and Myofibroblast Differentiation

Deployment-Related Constrictive Bronchiolitis as TGF-beta Activation and Myofibroblast Recruitment

Dupuytren Contracture as Myofibroblast Activation and Contraction

Endomyocardial Fibrosis as Fibroblast activation and excessive collagen deposition

Eosinophilic Fasciitis as TGF-beta-Driven Fascial Fibroblast Activation

Familial Vesicoureteral Reflux as Interstitial Myofibroblast Activation

Glycogen Storage Disease Type VI as Hepatic Stellate Cell Activation and Fibrogenesis

Hepatic Fibrinogen Storage Disease as Hepatic Stellate Cell Activation

Hepatic veno-occlusive disease-immunodeficiency syndrome as Hepatic stellate cell activation and fibrotic remodeling

Hypertrophic Cardiomyopathy 30, Atrial as Cardiac Fibroblast Activation

Idiopathic Interstitial Pneumonia as Myofibroblast activation in the fibrosing entities

Idiopathic Pulmonary Fibrosis as Fibroblast activation and myofibroblast differentiation

IgG4-Related Disease as Fibroblast Activation and Collagen Production

Liver Cirrhosis as Hepatic Stellate Cell Activation

Mucous Membrane Pemphigoid as Profibrotic Conjunctival Fibroblast Activation

Paraquat Poisoning as TGF-beta-Driven Mesenchymal Transition of Alveolar Epithelium

Progressive Familial Intrahepatic Cholestasis as Hepatic Stellate Cell Activation and Biliary Fibrosis

Proliferative Vitreoretinopathy as RPE Epithelial-Mesenchymal Transition

Raine Syndrome as Gingival Fibroblast Activation via TGF-beta and YAP/TAZ

Sarcoidosis as Fibrotic Tissue Remodeling

Silicosis as Fibroblast-to-Myofibroblast Activation

Sulfur Mustard Poisoning as TGF-beta Driven Myofibroblast Activation

Volumetric Muscle Loss as Myofibroblast Activation and Excessive Collagen Deposition

Wilson Disease as Hepatic Stellate Cell Activation

Downstream

Excessive ECM Deposition

Show evidence (3 references)

PMID:32673537 SUPPORT Other

"Cardiac fibrosis is mediated by the activation of resident cardiac fibroblasts, which differentiate into myofibroblasts in response to injury or stress. Although myofibroblast formation is a physiological response to acute injury, such as myocardial infarction, myofibroblast persistence, as..."

Demonstrates the conserved fibroblast-to-myofibroblast transition as the central effector mechanism, with the distinction between physiological (acute) and pathological (persistent) activation. Evidence source is OTHER because this is a review article.

PMID:33774068 SUPPORT Other

"One central pathway in remodelling processes involves transforming growth factor (TGF)-β induced fibroblast activation and myofibroblast differentiation that increases ECM production."

Confirms TGF-beta-induced fibroblast activation and myofibroblast differentiation as the central conserved pathway in tissue remodeling and fibrosis. Evidence source is OTHER because this is a review article.

PMID:33981032 SUPPORT Model Organism

"Mouse fibroblast atlases and a DptIRESCreERT2 knock-in mouse identified two universal fibroblast transcriptional subtypes across tissues."

Cross-species single-cell atlas evidence for the precursor-lineage substitution this node's description relies on: the fibroblast lineage itself is organized into shared transcriptional subtypes across tissues, which is why substituting the organ-specific precursor cell type here is a well-supported move rather than an assumption.

Excessive ECM Deposition

effector

Activated myofibroblasts produce excessive collagen (types I and III) and other extracellular matrix proteins while also secreting tissue inhibitors of metalloproteinases (TIMPs) that block matrix degradation. The imbalance between ECM production and degradation leads to progressive matrix accumulation. This process is conserved across organs though the specific collagen subtypes and matrix composition may vary.

Myofibroblast CL:0000186

ECM Organization GO:0030198 ↑ INCREASED Collagen Biosynthesis GO:0032964 ↑ INCREASED Collagen Fibril Organization GO:0030199 ↑ INCREASED

Used by disorders

Alcohol-Associated Liver Disease as Excessive Hepatic Extracellular Matrix Deposition

Asbestosis as Excessive extracellular matrix deposition

Asherman_Syndrome as Excessive Endometrial Matrix Deposition

Biliary Atresia as Fibro-obliteration of the Biliary Tree

Caroli disease as Progressive Peribiliary Fibrosis

Chagas disease as Myocardial fibrosis and arrhythmogenic substrate

Coal Workers Pneumoconiosis as Peribronchiolar Collagen Deposition and Coal Macule Formation

Congenital Merosin-deficient Muscular Dystrophy 1A as Endomysial Fibrosis and Replacement of Muscle

Deployment-Related Constrictive Bronchiolitis as Peribronchiolar Collagen Deposition

Dilated Cardiomyopathy 1P as Myocardial Replacement Fibrosis

Dupuytren Contracture as Excessive Collagen Deposition and Cord Formation

Endomyocardial Fibrosis as Dense endocardial fibrous scar

Familial Vesicoureteral Reflux as Renal Cortical Scarring

Hepatic Fibrinogen Storage Disease as Excessive Hepatic ECM Deposition

Hepatic veno-occlusive disease-immunodeficiency syndrome as Progressive hepatic fibrosis and organ dysfunction

Hypertrophic Cardiomyopathy 30, Atrial as Left Atrial Fibrosis

Idiopathic Hypereosinophilic Syndrome as Endomyocardial Fibrosis and Restrictive Physiology

Idiopathic Pulmonary Fibrosis as Excessive extracellular matrix deposition

IgG4-Related Disease as Storiform Fibrosis

Liver Cirrhosis as Excessive Hepatic ECM Deposition

Mitral Valve Prolapse as Regional Left Ventricular Fibrosis

Mucous Membrane Pemphigoid as Mucosal Subepithelial Fibrosis

Paraquat Poisoning as Progressive Pulmonary Fibrosis

Pericarditis as Fibrotic organization of the pericardium

Primary Aldosteronism as Myocardial and Renal Interstitial Fibrosis

Raine Syndrome as Excessive Gingival ECM Deposition and Calcification

Rheumatic Heart Disease as Chronic valve fibrosis, commissural fusion, and calcification

Silicosis as Excess Collagen Deposition and Silicotic Nodule Formation

Sulfur Mustard Poisoning as Bronchiolar and Interstitial Collagen Deposition

Uterine Leiomyoma as Excessive Extracellular Matrix Deposition and Tissue Stiffening

Volumetric Muscle Loss

Wilson Disease as Excessive Hepatic ECM Deposition

Downstream

Architectural Distortion and Organ Dysfunction

Show evidence (2 references)

PMID:33774068 SUPPORT Other

"Abnormal deposition of extracellular matrix (ECM) proteins is a key factor in the development of tissue remodelling that results in symptoms and impaired lung function in these diseases."

Establishes abnormal ECM deposition as the key factor in fibrotic tissue remodeling. Evidence source is OTHER because this is a review article synthesizing data across multiple pulmonary diseases.

PMID:21727191 SUPPORT Other

"Once fibroblasts become activated, they transform into α-smooth muscle actin–expressing myofibroblasts that secrete ECM components."

Directly describes activated myofibroblasts as the source of ECM production in fibrosis. Evidence source is OTHER because this is a review synthesizing human and model organism data.

Architectural Distortion and Organ Dysfunction

consequence

Progressive matrix accumulation distorts normal tissue architecture, leading to organ-specific structural changes: nodular regeneration and portal hypertension in liver, honeycombing in lung, interstitial expansion and stiffening in heart, glomerulosclerosis in kidney. The end result is irreversible loss of organ function. While the specific architectural consequences are organ-dependent, the underlying process of progressive structural distortion from excessive matrix is conserved.

Used by disorders

Alcohol-Associated Liver Disease as Cirrhotic Architectural Distortion and Functional Failure

Asbestosis as Interstitial fibrosis and architectural distortion

Asherman_Syndrome as Intrauterine Adhesion Formation

CAPN5-Related Vitreoretinopathy as Fibrotic Proliferative Vitreoretinopathy and Progressive Blindness

Coal Workers Pneumoconiosis as Nodule Coalescence into Progressive Massive Fibrosis

Deployment-Related Constrictive Bronchiolitis as Subepithelial Fibrosis and Smooth Muscle Hypertrophy Narrowing Membranous Bronchioles

Dupuytren Contracture as Digital Flexion Contracture and Hand Dysfunction

Endomyocardial Fibrosis as Apical and inflow-tract cavity obliteration

Familial Vesicoureteral Reflux as Reflux Nephropathy and Progressive Nephron Loss

Formaldehyde Poisoning as Fibrotic stricture formation

Idiopathic Interstitial Pneumonia as Progressive pulmonary fibrosis

Idiopathic Pulmonary Fibrosis as Architectural distortion and gas-exchange failure

Liver Cirrhosis as Cirrhotic Architectural Distortion

Pulmonary Alveolar Microlithiasis as Interstitial Fibrosis and Restrictive Physiology

Sulfur Mustard Poisoning as Bronchiolitis Obliterans and Progressive Airflow Obstruction

Volumetric Muscle Loss as Fibrotic Scar Replacement and Persistent Functional Deficit

Show evidence (2 references)

PMID:23255577 SUPPORT Other

"Fibrosis is a pathological scarring process that leads to destruction of organ architecture and impairment of organ function."

Directly states that fibrosis leads to destruction of organ architecture and impairment of function, the defining consequence of the fibrotic response module. Evidence source is OTHER because this is a review.

PMID:21727191 SUPPORT Other

"Fibrosis develops when the wound is severe, the tissue-damaging irritant persists, or when the repair process becomes dysregulated."

Establishes that architectural distortion and organ dysfunction result from persistent or dysregulated wound repair rather than the normal healing process.