High Altitude Pulmonary Edema

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Subtypes

2

Classic (lowlander ascent) HAPE

The common form, affecting non-acclimatised lowlanders after rapid ascent above 2,500-3,000 m. This is the presentation the pathophysiology and treatment sections describe by default.

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"The first and most common form affects non-acclimatized lowlanders following a rapid ascent above 2500–3000 m."

Defines the common lowlander-ascent form as one of two recognised onset patterns.

Re-entry HAPE (highland dwellers returning to altitude)

Occurs in highland residents who descend to low altitude and then reascend. The at-risk population is the inverse of the classic form - people acclimatised by residence who have lost that acclimatisation - which is what makes it worth separating, since it changes who should be counselled about prophylaxis. The mechanism is regarded as the same, so this is a variant of population and presentation rather than of pathophysiology.

Show evidence (2 references)

PMID:42254115 SUPPORT Human Clinical

"The second form, referred to as re-entry HAPE, is observed in highland dwellers who reascend after a period of time at sea level."

Defines re-entry HAPE and its distinct at-risk population.

PMID:42254115 SUPPORT Human Clinical

"The pathophysiological mechanism is likely identical for both types"

Supports treating re-entry HAPE as a population variant rather than a mechanistically distinct disease; the authors' hedge is preserved.

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Mechanistic Hypotheses

2

Capillary stress failure is the primary lesion, inflammation secondary

pressure_primary_model CANONICAL

HAPE begins as a hemodynamic disease: exaggerated, uneven hypoxic vasoconstriction raises pulmonary capillary pressure past the mechanical tolerance of the blood-gas barrier, and inflammation follows the resulting stress failure. The decisive evidence is that transcapillary protein escape is still normal in susceptible subjects whose capillary pressure has already risen, and that agents which lower pulmonary artery pressure prevent the disease while anti-inflammatory action alone does not account for the benefit.

Inflammation contributes to initiation rather than only amplifying

inflammation_primary_model ALTERNATIVE

A minority view holds that immune dysregulation contributes to the initiation of barrier failure rather than merely amplifying it, supported by elevated IL-2, IL-10, and TNF in HAPE patients and by cytokine profiles that discriminate cases from acclimatized controls with high accuracy. The unresolved problem is temporal: the human cytokine data are cross-sectional in established disease and cannot separate cause from consequence, and lavage inflammation appears after the pressure rise in the studies that measured both.

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Discussions and Knowledge Gaps

2

Does the individual variation in hypoxic pulmonary vasoreactivity that determines HAPE susceptibility have a tractable molecular basis, and can it be measured at low altitude to predict risk before travel?

KNOWLEDGE GAP hape_susceptibility_vasoreactivity_basis

Attached to

pathophysiology#Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction

Susceptibility is reproducible within individuals and is the single largest determinant of who develops HAPE, yet prophylaxis is currently offered on the basis of prior episodes rather than any prospective measurement. Enhanced hypoxic vasoreactivity is already detectable at low altitude in susceptible subjects, so a predictive test is physiologically plausible; what is missing is a validated threshold and an understanding of what sets the reactivity.

Can a lung-on-chip that applies hypoxia directly to the alveolar barrier be treated as a model of HAPE, when the human disease is initiated by capillary overperfusion rather than by hypoxia acting on the barrier?

HUMAN MODEL MISMATCH hape_chip_lacks_hemodynamic_initiation

Attached to

experimental_models#Hypoxia-exposed lung-on-chip model of blood-gas barrier dysfunction pathophysiology#Capillary Stress Failure of the Blood-Gas Barrier

The chip reproduces hypoxia-driven barrier protein loss and responds to perfluorocarbon, but it has no pulmonary circulation and therefore cannot generate the uneven vasoconstriction and regional capillary hypertension that the human evidence identifies as the initiating lesion. The mismatch matters because a therapeutic that works by protecting the barrier against direct hypoxic injury need not work against a mechanically overloaded barrier. A chip incorporating controllable perfusion pressure across a capillary network would test whether the same protection holds when the insult is hemodynamic.

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Pathophysiology

7

Sustained Alveolar Hypoxia at Altitude

Rapid ascent lowers barometric pressure and therefore inspired oxygen tension, producing sustained alveolar hypoxia. Exercise during ascent aggravates it by raising cardiac output and pulmonary blood flow through an already hypoxic vascular bed. This is the environmental trigger; no host lesion is required.

Response to hypoxia GO:0001666 ↑ INCREASED Cellular response to hypoxia GO:0071456 ↑ INCREASED

Lung UBERON:0002048

Downstream

Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction Alveolar hypoxia is the direct stimulus for hypoxic pulmonary vasoconstriction; in susceptible individuals the response is disproportionate.

Show evidence (1 reference)

PMID:39331568 SUPPORT Other

"Exposure to hypobaric hypoxia, especially when associated with exercise, is a condition potentially leading to the development of the so-called high-altitude pulmonary edema (HAPE)."

Identifies hypobaric hypoxia, aggravated by exercise, as the initiating exposure.

Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction

Hypoxic pulmonary vasoconstriction is normally a matching reflex that diverts perfusion away from poorly ventilated lung. In HAPE-susceptible individuals the response is both excessive in magnitude and regionally heterogeneous. Reduced nitric oxide bioavailability and increased endothelin-1 shift the vasomotor balance toward constriction. The heterogeneity is the pathogenically important feature: it is what converts a global rise in pulmonary vascular resistance into focal capillary overperfusion rather than an evenly shared pressure load.

Smooth muscle cell of the pulmonary artery CL:0002591 Pulmonary artery endothelial cell CL:1001568

Nitric oxide biosynthetic process GO:0006809 ↓ DECREASED

Lung UBERON:0002048

Downstream

Pulmonary Capillary Hypertension and Regional Overperfusion Uneven precapillary constriction concentrates the cardiac output in the unconstricted capillary segments, raising pressure there rather than distributing it.

Show evidence (1 reference)

PMID:1922223 SUPPORT Human Clinical

"Exaggerated pulmonary-artery pressure due to hypoxic vasoconstriction is considered an important pathogenetic factor in high-altitude pulmonary edema."

States the exaggerated hypoxic vasoconstriction this node describes as an accepted pathogenetic factor.

Pulmonary Capillary Hypertension and Regional Overperfusion

Pulmonary capillary pressure rises well above normal. In the Capanna Regina Margherita study, every susceptible subject who went on to develop HAPE had a measured capillary pressure above 19 mmHg while every susceptible subject who did not remained below it — a separation clean enough to make capillary pressure the proximate determinant rather than a correlate. This is a precapillary, not a postcapillary, hypertension: left atrial pressure is normal, which is what makes the resulting edema non-cardiogenic.

Pulmonary capillary endothelial cell CL:4028001

Lung UBERON:0002048

Downstream

Capillary Stress Failure of the Blood-Gas Barrier Transmural pressure in the overperfused capillary segments exceeds the mechanical tolerance of the thin portion of the blood-gas barrier.

Show evidence (1 reference)

PMID:11319198 SUPPORT Human Clinical

"HAPE is initially caused by an increase in pulmonary capillary pressure."

The study's own conclusion that capillary hypertension is the initiating hemodynamic lesion.

Capillary Stress Failure of the Blood-Gas Barrier

Mechanical overload of the alveolar-capillary membrane disrupts the endothelial and epithelial layers and their shared basement membrane — stress failure in West's sense, a physical rupture rather than a signalled junctional opening, although junctional loss accompanies it. The barrier stops excluding protein and erythrocytes, which is why HAPE lavage fluid is high-protein and often blood-tinged. This is the node at which HAPE joins the shared blood-gas barrier pathway, and where a hypoxia-driven disease and a toxicant- or pathogen-driven one become mechanistically the same lesion.

Pulmonary capillary endothelial cell CL:4028001 Pulmonary alveolar type 1 cell CL:0002062 Pulmonary alveolar type 2 cell CL:0002063

Tight junction organization GO:0120193 ↓ DECREASED Adherens junction organization GO:0034332 ↓ DECREASED

Cell-cell junction GO:0005911

Alveolus of lung UBERON:0002299

Experimental models

Hypoxia-exposed lung-on-chip model of blood-gas barrier dysfunction ORGAN ON CHIP Reproduces hypoxia-driven loss of blood-gas barrier proteins and its pharmacological reversal.

Downstream

High-Permeability Alveolar Flooding and Hypoxemia A failed barrier passes protein-rich fluid and red cells into the interstitium and airspace.

Secondary Inflammatory Amplification Barrier failure exposes the airspace to plasma constituents and cell debris, recruiting an inflammatory response that follows rather than precedes the lesion.

Show evidence (1 reference)

PMID:11319198 SUPPORT Human Clinical

"The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did not differ significantly from the control subjects."

Normal transcapillary protein escape at a stage when capillary pressure is already elevated is the key negative result placing barrier failure downstream of pressure, not as a primary defect.

Impaired Alveolar Fluid Clearance

Hypoxia downregulates the amiloride-sensitive epithelial sodium channel and Na+/K+-ATPase-driven transepithelial sodium transport that normally drives water out of the airspace. Reduced clearance does not by itself cause HAPE but determines how much fluid accumulates once the barrier has failed, and it is the rationale for beta-agonist prophylaxis. Its contribution is secondary to the hemodynamic lesion: in the tadalafil and dexamethasone prophylaxis trial, both drugs prevented HAPE while producing no measurable change in nasal potential difference, the surrogate for alveolar sodium transport.

Pulmonary alveolar type 2 cell CL:0002063

Sodium ion transmembrane transport GO:0035725 ↓ DECREASED

Alveolus of lung UBERON:0002299

Downstream

High-Permeability Alveolar Flooding and Hypoxemia Reduced active sodium and water reabsorption slows resolution of alveolar fluid, deepening the flooding produced by the barrier lesion.

Show evidence (1 reference)

PMID:17015867 SUPPORT Human Clinical

"No statistically significant difference between groups was found in change in nasal potentials and expression of leukocyte sodium transport protein messenger RNA."

Effective prophylaxis without any measurable change in the sodium-transport surrogate supports treating impaired clearance as a modifier rather than the primary lesion; PARTIAL because a null result in a 29-subject trial is weak evidence.

Secondary Inflammatory Amplification

Once the barrier has failed, plasma proteins, cell-free DNA, and debris in the airspace recruit neutrophils and raise circulating cytokines. This amplifies injury and impairs resolution, but it is a consequence of the mechanical lesion, not its cause — the distinction that separates HAPE from ARDS and explains why anti-inflammatory prophylaxis is not the mainstay. Dexamethasone is the partial exception, and its prophylactic benefit tracks with pulmonary artery pressure reduction rather than with an anti-inflammatory effect.

Inflammatory response GO:0006954 ↑ INCREASED Leukocyte migration GO:0050900 ↑ INCREASED

Alveolus of lung UBERON:0002299

Downstream

High-Permeability Alveolar Flooding and Hypoxemia Inflammatory mediators further increase permeability and impede clearance, worsening flooding already initiated mechanically.

Show evidence (1 reference)

PMID:40752453 SUPPORT Human Clinical

"CONCLUSIONS: Elevated IL-2, IL-10, and TNF in HAPE patients underscore immune dysregulation as a disease driver."

Establishes measurable immune dysregulation in HAPE patients; the authors' framing as a driver is their interpretation of a cross-sectional comparison.

High-Permeability Alveolar Flooding and Hypoxemia

Protein-rich, often erythrocyte-containing fluid fills the interstitium and alveoli in a characteristically patchy distribution that mirrors the uneven perfusion that produced it. Flooded alveoli are perfused but not ventilated, creating shunt, and the resulting hypoxemia deepens alveolar hypoxia and so intensifies hypoxic vasoconstriction — a positive feedback loop that accounts for the rapid clinical deterioration and for why descent or oxygen, which break the loop at its origin, are so effective.

Respiratory gaseous exchange by respiratory system GO:0007585 ↓ DECREASED

Alveolus of lung UBERON:0002299 Lung UBERON:0002048

Animal models

Canine hypobaric HAPE model (simulated 6000 m) Dog recapitulates Reproduces the hypobaric-hypoxia-induced accumulation of extravascular lung water that defines the human syndrome.

Downstream

Sustained Alveolar Hypoxia at Altitude Shunt-driven hypoxemia worsens alveolar hypoxia, closing a self-amplifying loop back onto the initiating trigger.

Show evidence (1 reference)

PMID:39331568 SUPPORT Other

"A model is also presented to characterize HAPE nonsusceptible versus susceptible individuals based on the efficiency of alveolar-capillary oxygen uptake and estimated morphology of the air-blood barrier."

Frames the clinical outcome in terms of alveolar-capillary oxygen uptake efficiency, the gas-exchange endpoint this node describes.

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Pathograph

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Phenotypes

6

Cardiovascular 2

Pulmonary Arterial Hypertension VERY_FREQUENT HP:0002092

Temporal: ACUTE

Show evidence (1 reference)

PMID:1922223 SUPPORT Human Clinical

"CONCLUSIONS: The prophylactic administration of nifedipine is effective in lowering pulmonary-artery pressure and preventing high-altitude pulmonary edema in susceptible subjects."

Elevated pulmonary artery pressure is the treatment target in HAPE, establishing it as a cardinal feature.

Tachycardia FREQUENT HP:0001649

Show evidence (2 references)

PMID:42254115 SUPPORT Human Clinical

"concurrent with at least two physical signs, including inspiratory crackles, central cyanosis, tachypnea, or tachycardia"

Tachycardia is one of the physical signs the clinical diagnostic criteria for HAPE draw on, establishing it as a recognised feature rather than an incidental finding.

PMID:41316096 SUPPORT Human Clinical

"physical examination: central cyanosis, shortness of breath, tachycardia, decreased breath sounds, and audible wet rales in the lungs during the stage of alveolar edema"

Lists tachycardia among the examination findings in the diagnostic criteria used by this 411-patient cohort.

Metabolism 1

Pulmonary Edema OBLIGATE HP:0100598

Temporal: ACUTE

Show evidence (1 reference)

PMID:11319198 SUPPORT Human Clinical

"BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension and bronchoalveolar lavage fluid changes indicative of inflammation."

Confirms pulmonary edema as the defining feature of the syndrome.

Respiratory 2

Hypoxemia VERY_FREQUENT HP:0012418

Show evidence (1 reference)

PMID:40938265 SUPPORT Human Clinical

"Sixty-four dyspneic adults with maximum oxygen saturation < 85%, recent arrival at high altitude, and noncardiogenic pulmonary edema on chest radiography were randomized to receive CPAP treatment plus usual care or usual care (oxygen-only) delivered through a sham CPAP mask."

An oxygen saturation below 85% was the enrolment threshold, documenting severe hypoxemia as a defining clinical feature.

Cough FREQUENT HP:0012735

Show evidence (2 references)

PMID:41316096 SUPPORT Human Clinical

"High-altitude pulmonary edema (HAPE) is characterized by loss of stamina, dyspnea, and dry cough during exertion, followed by dyspnea at rest, rales, cyanosis, cough, and pink, frothy sputum"

Describes the characteristic progression from dry exertional cough to productive cough with pink frothy sputum, which is the phenotype this entry records.

PMID:41316096 SUPPORT Human Clinical

"Early symptoms include excessive exertional dyspnoea in relation to the patient’s companions, mild cough, chest tightness and reduced exercise performance."

Establishes that cough is present from the early stage as a mild, exertional symptom, before the productive phase the first quote describes.

Other 1

Exertional Dyspnea VERY_FREQUENT HP:0002875

Show evidence (1 reference)

PMID:40938265 SUPPORT Human Clinical

"Sixty-four dyspneic adults with maximum oxygen saturation < 85%, recent arrival at high altitude, and noncardiogenic pulmonary edema on chest radiography were randomized to receive CPAP treatment plus usual care or usual care (oxygen-only) delivered through a sham CPAP mask."

The trial's enrolment criteria establish dyspnea as a defining presenting feature of HAPE.

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Genetic Associations

3

JAK2

Gene: JAK2 hgnc:6192 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"A genetic predisposition is also recognized, linked to specific mutations such as those in the JAK2 gene, P1B1 cytochrome genes, and a deletion in the histidine-rich glycoprotein gene, the latter of which is associated with an earlier onset of the condition"

Names JAK2 among recognised predisposing loci; graded PARTIAL because the case series cites this secondarily rather than reporting a primary association study.

HRG

Gene: HRG hgnc:5181 relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"a deletion in the histidine-rich glycoprotein gene, the latter of which is associated with an earlier onset of the condition"

Reports the HRG deletion and its association with earlier onset; PARTIAL for the same secondary-citation reason.

Unidentified cytochrome P450 locus

relationship_type: SUSCEPTIBILITY

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"A genetic predisposition is also recognized, linked to specific mutations such as those in the JAK2 gene, P1B1 cytochrome genes, and a deletion in the histidine-rich glycoprotein gene"

Names the cytochrome locus among recognised predispositions; PARTIAL because the symbol is printed non-canonically and the citation is secondary.

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Medical Actions

6

Descent and Supplemental Oxygen

Action: Oxygen Therapy NCIT:C94624

Immediate descent is the definitive treatment and reverses the disease by removing the hypoxic stimulus. Where descent is impossible, supplemental oxygen, and portable hyperbaric therapy where available, substitute for it. Both act at the top of the causal chain rather than on the edema itself.

Mechanism Target:

INHIBITS Sustained Alveolar Hypoxia at Altitude — Raising inspired oxygen tension abolishes the hypoxic stimulus for pulmonary vasoconstriction and breaks the hypoxemia feedback loop.

Show evidence (1 reference)

PMID:40938265 SUPPORT Human Clinical

"CONCLUSION: Both CPAP with high-flow oxygen and high-flow oxygen alone are highly effective for the treatment of HAPE."

A randomized trial establishing high-flow oxygen alone as highly effective treatment.

Continuous Positive Airway Pressure

Action: Continuous Positive Airway Pressure NCIT:C124040

CPAP added to high-flow oxygen was tested in a randomized trial against sham CPAP with high-flow oxygen. It did not accelerate resolution beyond oxygen alone, so it is not an established addition where oxygen is available; the trial is recorded here because the negative result is the clinically useful finding.

Mechanism Target:

INHIBITS High-Permeability Alveolar Flooding and Hypoxemia — Positive airway pressure recruits flooded alveoli and reduces shunt, acting on the gas-exchange consequence rather than the vascular cause.

Show evidence (1 reference)

PMID:40938265 SUPPORT Human Clinical

"RESULTS: HAPE resolution in the CPAP plus high FiO2 group and the high flow oxygen alone group was similar."

The trial found no advantage of adding CPAP to high-flow oxygen; PARTIAL records an effective but not additive intervention.

Nifedipine Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: nifedipine CHEBI:7565

A dihydropyridine calcium channel blocker that lowers pulmonary artery pressure. In susceptible mountaineers ascending rapidly to 4,559 m it cut HAPE incidence from 7 of 11 on placebo to 1 of 10. It remains the standard pharmacologic prophylaxis for individuals with a HAPE history.

Mechanism Target:

INHIBITS Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction — Calcium channel blockade relaxes pulmonary arterial smooth muscle, lowering the pressure that drives capillary stress failure.

Show evidence (1 reference)

PMID:1922223 SUPPORT Human Clinical

"Seven of the 11 subjects who received placebo but only 1 of the 10 subjects who received nifedipine had pulmonary edema at 4559 m (P = 0.01)."

A randomized placebo-controlled result directly demonstrating prophylactic efficacy.

Tadalafil Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: tadalafil CHEBI:71940

A phosphodiesterase-5 inhibitor that potentiates nitric-oxide-mediated pulmonary vasodilation, addressing the reduced nitric oxide bioavailability that underlies exaggerated hypoxic vasoconstriction. An alternative to nifedipine in susceptible individuals.

Mechanism Target:

INHIBITS Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction — PDE5 inhibition raises cGMP in pulmonary vascular smooth muscle, opposing hypoxic vasoconstriction.

Show evidence (1 reference)

PMID:17015867 SUPPORT Human Clinical

"High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo)."

Randomized evidence of prophylactic efficacy for both tadalafil and dexamethasone.

Dexamethasone Prophylaxis

Action: Pharmacotherapy NCIT:C15986

Agent: dexamethasone CHEBI:41879

A glucocorticoid that prevented HAPE outright in the same randomized trial and also lowered systolic pulmonary artery pressure. Notably its benefit tracked with the hemodynamic effect and not with any measurable change in alveolar sodium transport, which is part of why the pressure mechanism is considered primary.

Mechanism Target:

INHIBITS Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction — Reduces the rise in systolic pulmonary artery pressure on ascent.

Show evidence (1 reference)

PMID:17015867 SUPPORT Human Clinical

"CONCLUSIONS: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure and may reduce the incidence of HAPE in adults with a history of HAPE."

The trial's conclusion ties the prophylactic benefit to a reduction in systolic pulmonary artery pressure, the proposed mechanism.

Furosemide

Action: Pharmacotherapy NCIT:C15986

Agent: furosemide CHEBI:47426

A loop diuretic used adjunctively in some centres. A retrospective cohort of 273 HAPE inpatients found lower CT severity scores with furosemide, but the evidence is observational and its effect on outcome is unestablished; it is not a substitute for descent or oxygen.

Mechanism Target:

INHIBITS High-Permeability Alveolar Flooding and Hypoxemia — Diuresis reduces pulmonary vascular filling pressure and total lung water, acting on the accumulated edema rather than its cause.

Show evidence (1 reference)

PMID:38438895 SUPPORT Human Clinical

"CONCLUSION: Furosemide helps alleviate pulmonary edema in HAPE patients, but further research is needed to clarify its impact on prognosis."

A retrospective cohort supporting radiographic benefit while explicitly leaving prognosis unresolved; PARTIAL reflects the authors' own hedge.

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Environmental Factors

1

Rapid Ascent to High Altitude

Deliberately left unbound. ECTO and XCO were both searched (2026-08) for a high-altitude or hypobaric-hypoxia exposure class and neither has one. The closest XCO candidates are experimental apparatus and condition terms (XCO:0001406 hypobaric chamber, XCO:0000010 controlled air oxygen content) that describe a laboratory manipulation rather than the natural environmental exposure a traveller undergoes, so binding one would misdescribe the exposure. Revisit if ECTO adds an altitude exposure class.

Ascent above roughly 2,500-3,000 m, particularly when rapid and combined with exertion, is the necessary environmental exposure - necessary but not sufficient, since HAPE strikes only a susceptible minority of those who ascend, which is what the susceptibility loci and the vasoreactivity knowledge gap are about. Rate of ascent, absolute altitude attained, sleeping altitude, and exertion during ascent are each independent determinants of risk, which is why staged ascent and preacclimatization are effective prevention.

Show evidence (1 reference)

PMID:38682380 SUPPORT Other

"a multipronged approach including pharmacologic prophylaxis, careful planning about the rate of ascent, and the degree of physical effort and other strategies, such as preacclimatization, staged ascent, and use of hypoxic tents, can be employed to reduce the risk of recurrence with future travel"

That modifying rate of ascent, exertion, and acclimatization reduces recurrence risk establishes these exposure parameters as causal determinants.

Mechanism Target:

TRIGGERS Sustained Alveolar Hypoxia at Altitude — The fall in barometric pressure on ascent is what lowers alveolar oxygen tension; the exposure and the trigger node are the same physical event.

Show evidence (1 reference)

PMID:39331568 SUPPORT Other

"Exposure to hypobaric hypoxia, especially when associated with exercise, is a condition potentially leading to the development of the so-called high-altitude pulmonary edema (HAPE)."

Directly ties the hypobaric hypoxia exposure to HAPE development.

🔬

Diagnosis

1

Clinical diagnosis of HAPE (PRESENT)

HAPE is a clinical diagnosis; there is no gold-standard test. It requires recent rapid ascent above roughly 2,500-3,000 m within one to five days, a qualifying combination of symptoms and physical signs, radiographic non-cardiogenic pulmonary oedema, exclusion of ARDS, cardiogenic oedema and severe pneumonia, and improvement on descent or oxygen. The symptom-plus-sign threshold is what separates it from ordinary altitude breathlessness.

The five-point criteria used by the 411-patient Qinghai inpatient cohort (PMID:41316096) add the recent-ascent window, chest CT or radiograph findings, exclusion of ARDS, cardiogenic pulmonary oedema and severe pneumonia, and symptom remission on transfer to low altitude.

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"A clinical diagnosis of HAPE requires the presence of a minimum of two symptoms, such as dyspnea at rest, cough, weakness, reduced exertional tolerance, or chest tightness, concurrent with at least two physical signs, including inspiratory crackles, central cyanosis, tachypnea, or tachycardia"

States the two-symptom plus two-sign threshold that defines the clinical diagnosis.

📊

Prevalence

2

Global travellers to high altitude

Period Prevalence Unknown

Reported incidence spans three orders of magnitude because it is conditioned on ascent rate, individual susceptibility, and the altitude reached rather than on a fixed denominator population. Recorded as a range rather than a point estimate for that reason.

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"The reported incidence of HAPE varies widely across the global population, ranging from less than 0.01% to as high as 31%, depending on the rate of ascent, individual susceptibility, and the final altitude achieved"

Gives the reported incidence range and names the three determinants that make a single population figure meaningless for this disease.

Trekkers and mountaineers ascending faster than 600 m per day in the Himalayas and Alps

Period Prevalence 4000.0 per 100,000 >1 in 1,000

Approximately 4 percent in a defined rapid-ascent population. This is the figure to use when a denominator is needed, because unlike the global range it is conditioned on a stated ascent rate.

Show evidence (1 reference)

PMID:42254115 SUPPORT Human Clinical

"Among trekkers and mountaineers in the Himalayas and Alps who ascend at a rate exceeding 600 m per day, the incidence of HAPE is approximately 4%."

A rate-conditioned incidence estimate in a defined at-risk population.

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Experimental Models

1

Hypoxia-exposed lung-on-chip model of blood-gas barrier dysfunction ORGAN_ON_CHIP namo:OrganOnChip

A microfluidic lung-on-chip exposed to 3% oxygen for 24 hours to recapitulate hypoxic lung injury at the organ level, used alongside a canine HAPE model to test perfluorocarbon and to localize its effect to the HIF-1-alpha/HO-1 pathway. The chip isolates the direct effect of hypoxia on the barrier from the hemodynamic overperfusion that drives HAPE in vivo, which is both what makes it informative and what bounds it.

Organism

human NCBITaxon:9606

Tissue

alveolus of lung UBERON:0002299

Culture

Microfluidic lung-on-chip under hypoxic gas control

Publication

PMID:41786071

Pathograph links

Capillary Stress Failure of the Blood-Gas Barrier partially recapitulates fidelity: moderate Reproduces hypoxia-driven loss of blood-gas barrier proteins and its pharmacological reversal.

Limitations: The chip applies hypoxia directly to the barrier and has no pulmonary circulation, so it cannot reproduce the exaggerated, spatially uneven hypoxic vasoconstriction and capillary overperfusion that are the actual initiating lesion in HAPE. It therefore models the downstream barrier consequence of hypoxia, not the hemodynamic cause.

Readouts

Blood-gas barrier-related protein expression

Direction: DECREASED

Interpretation: Loss of barrier proteins under hypoxia is the molecular correlate of the barrier-failure node.

Show evidence (1 reference)

PMID:41786071 SUPPORT In Vitro

"Then, the latter model was exposed to hypoxia (3% oxygen; 24 h) and co-cultured with 10% PFC."

Documents the hypoxic exposure protocol under which the barrier readout was measured.

Show evidence (1 reference)

PMID:41786071 SUPPORT In Vitro

"Next, we created a lung-on-chip model that allowed lung injury to be recapitulated in vitro at the organ level."

Establishes the chip as an organ-level model of the hypoxic lung injury this node describes.

Show evidence (1 reference)

PMID:41786071 SUPPORT In Vitro

"In addition, we found that PFC blocked activation of the hypoxia-inducible factor-1α (HIF-1α)/heme oxygenase-1 (HO-1) signaling pathway."

The chip localized the therapeutic effect to a specific signaling pathway, supporting its inclusion as a mechanistically informative model.

🐁

Animal Models

1

Canine hypobaric HAPE model (simulated 6000 m)

Beagles exposed to a simulated altitude of 6,000 m for 48 hours develop increased lung water content, raised lung injury scores, inflammatory cytokine release, and loss of blood-gas barrier proteins. Used as the in vivo arm of the perfluorocarbon study.

Species

Dog

Publication

PMID:41786071

Pathograph links

High-Permeability Alveolar Flooding and Hypoxemia recapitulates fidelity: moderate Reproduces the hypobaric-hypoxia-induced accumulation of extravascular lung water that defines the human syndrome.

Limitations: A 48-hour exposure to a simulated 6,000 m in an anesthetized large-animal preparation compresses a clinical course that in humans unfolds over two to four days of active ascent, and the model does not select for the individual hypoxic vasoreactivity that determines human susceptibility.

Readouts

Lung water content and lung injury score

Direction: INCREASED

Interpretation: Direct measurement of the alveolar flooding endpoint under hypobaric hypoxia.

Show evidence (1 reference)

PMID:41786071 SUPPORT Model Organism

"We exposed beagle dogs to a simulated altitude of 6000 m for 48 h to establish the HAPE model and treated them with vaporized PFC."

Documents the exposure protocol establishing the canine HAPE model.

{ }

Source YAML

click to show

name: High Altitude Pulmonary Edema
creation_date: "2026-08-27T00:00:00Z"
category: Environmental
disease_term:
  preferred_term: high altitude pulmonary edema
  term:
    id: MONDO:0031257
    label: high altitude pulmonary edema
parents:
- Acute Altitude Illness
- Pulmonary Edema
- Respiratory Disease
description: >-
  High altitude pulmonary edema (HAPE) is a non-cardiogenic pulmonary edema that
  develops in otherwise healthy people within two to four days of rapid ascent,
  typically above 2,500-3,000 m. It is the leading cause of death from altitude
  illness. The initiating lesion is not inflammatory and not a permeability
  defect: sustained alveolar hypoxia provokes an exaggerated and, critically,
  spatially uneven hypoxic pulmonary vasoconstriction, so that the fraction of
  the pulmonary capillary bed that escapes constriction receives the whole
  cardiac output at high pressure. Capillary pressure rises past the threshold
  the blood-gas barrier can mechanically withstand, the barrier undergoes stress
  failure, and a high-permeability, protein- and erythrocyte-rich edema follows.
  Inflammation appears afterwards and amplifies the lesion rather than starting
  it — the ordering established by the observation that transcapillary protein
  escape is still normal in susceptible subjects whose capillary pressure has
  already risen. Impaired alveolar sodium and fluid reabsorption is a
  co-contributor, reducing the lung's ability to clear the fluid once it forms.
  Susceptibility is individual and reproducible, tracking with the magnitude of
  a person's hypoxic pulmonary vasoreactivity, which is why prophylaxis works by
  lowering pulmonary artery pressure (nifedipine, tadalafil) rather than by
  targeting inflammation. Descent and supplemental oxygen remain the definitive
  treatment.

pathophysiology:
- name: Sustained Alveolar Hypoxia at Altitude
  description: >-
    Rapid ascent lowers barometric pressure and therefore inspired oxygen
    tension, producing sustained alveolar hypoxia. Exercise during ascent
    aggravates it by raising cardiac output and pulmonary blood flow through an
    already hypoxic vascular bed. This is the environmental trigger; no host
    lesion is required.
  role: trigger
  biological_scale: ORGANISM
  conforms_to: "alveolar_capillary_barrier_failure#Alveolar-Capillary Interface Insult"
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: Response to hypoxia
    term:
      id: GO:0001666
      label: response to hypoxia
    modifier: INCREASED
  - preferred_term: Cellular response to hypoxia
    term:
      id: GO:0071456
      label: cellular response to hypoxia
    modifier: INCREASED
  downstream:
  - target: Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
    causal_link_type: DIRECT
    description: >-
      Alveolar hypoxia is the direct stimulus for hypoxic pulmonary
      vasoconstriction; in susceptible individuals the response is
      disproportionate.
    evidence:
    - reference: PMID:17015867
      reference_title: "Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary
        edema: a randomized trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction
        associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption
        of alveolar fluid.
      explanation: States the causal chain from hypoxia to exaggerated vasoconstriction that this edge
        asserts.
  evidence:
  - reference: PMID:39331568
    reference_title: Physiopathology of high-altitude pulmonary edema.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: Exposure to hypobaric hypoxia, especially when associated with exercise, is a condition potentially
      leading to the development of the so-called high-altitude pulmonary edema (HAPE).
    explanation: Identifies hypobaric hypoxia, aggravated by exercise, as the initiating exposure.

- name: Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
  description: >-
    Hypoxic pulmonary vasoconstriction is normally a matching reflex that
    diverts perfusion away from poorly ventilated lung. In HAPE-susceptible
    individuals the response is both excessive in magnitude and regionally
    heterogeneous. Reduced nitric oxide bioavailability and increased
    endothelin-1 shift the vasomotor balance toward constriction. The
    heterogeneity is the pathogenically important feature: it is what converts a
    global rise in pulmonary vascular resistance into focal capillary
    overperfusion rather than an evenly shared pressure load.
  role: mediator
  biological_scale: TISSUE
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: Smooth muscle cell of the pulmonary artery
    term:
      id: CL:0002591
      label: smooth muscle cell of the pulmonary artery
  - preferred_term: Pulmonary artery endothelial cell
    term:
      id: CL:1001568
      label: pulmonary artery endothelial cell
  biological_processes:
  - preferred_term: Nitric oxide biosynthetic process
    term:
      id: GO:0006809
      label: nitric oxide biosynthetic process
    modifier: DECREASED
  downstream:
  - target: Pulmonary Capillary Hypertension and Regional Overperfusion
    causal_link_type: DIRECT
    description: >-
      Uneven precapillary constriction concentrates the cardiac output in the
      unconstricted capillary segments, raising pressure there rather than
      distributing it.
    evidence:
    - reference: PMID:11319198
      reference_title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: The HAPE-susceptible subjects, compared with the control subjects, had an enhanced pulmonary
        vasoreactivity to inspiratory hypoxia at low altitude and higher mean pulmonary artery pressures
      explanation: Links measured hypoxic vasoreactivity in susceptible subjects to the elevated pulmonary
        arterial pressures this edge produces.
  evidence:
  - reference: PMID:1922223
    reference_title: Prevention of high-altitude pulmonary edema by nifedipine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Exaggerated pulmonary-artery pressure due to hypoxic vasoconstriction is considered an important
      pathogenetic factor in high-altitude pulmonary edema.
    explanation: States the exaggerated hypoxic vasoconstriction this node describes as an accepted
      pathogenetic factor.

- name: Pulmonary Capillary Hypertension and Regional Overperfusion
  description: >-
    Pulmonary capillary pressure rises well above normal. In the Capanna Regina
    Margherita study, every susceptible subject who went on to develop HAPE had
    a measured capillary pressure above 19 mmHg while every susceptible subject
    who did not remained below it — a separation clean enough to make capillary
    pressure the proximate determinant rather than a correlate. This is a
    precapillary, not a postcapillary, hypertension: left atrial pressure is
    normal, which is what makes the resulting edema non-cardiogenic.
  role: mediator
  biological_scale: TISSUE
  locations:
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  cell_types:
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  downstream:
  - target: Capillary Stress Failure of the Blood-Gas Barrier
    causal_link_type: DIRECT
    description: >-
      Transmural pressure in the overperfused capillary segments exceeds the
      mechanical tolerance of the thin portion of the blood-gas barrier.
    evidence:
    - reference: PMID:11319198
      reference_title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: All of them had a pulmonary capillary pressure >19 mm Hg (range 20 to 26 mmHg), whereas
        all 7 susceptible subjects without HAPE had a pulmonary capillary pressure < 19 mm Hg (range 14
        to 18 mm Hg).
      explanation: The complete separation of HAPE and non-HAPE susceptible subjects by capillary pressure
        supports pressure as the proximate cause of the subsequent barrier lesion.
  evidence:
  - reference: PMID:11319198
    reference_title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: HAPE is initially caused by an increase in pulmonary capillary pressure.
    explanation: The study's own conclusion that capillary hypertension is the initiating hemodynamic
      lesion.

- name: Capillary Stress Failure of the Blood-Gas Barrier
  description: >-
    Mechanical overload of the alveolar-capillary membrane disrupts the
    endothelial and epithelial layers and their shared basement membrane —
    stress failure in West's sense, a physical rupture rather than a signalled
    junctional opening, although junctional loss accompanies it. The barrier
    stops excluding protein and erythrocytes, which is why HAPE lavage fluid is
    high-protein and often blood-tinged. This is the node at which HAPE joins
    the shared blood-gas barrier pathway, and where a hypoxia-driven disease and
    a toxicant- or pathogen-driven one become mechanistically the same lesion.
  role: mediator
  biological_scale: CELLULAR
  conforms_to: "alveolar_capillary_barrier_failure#Alveolar Epithelial and Endothelial Junctional Disruption"
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  cell_types:
  - preferred_term: Pulmonary capillary endothelial cell
    term:
      id: CL:4028001
      label: pulmonary capillary endothelial cell
  - 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
  biological_processes:
  - preferred_term: Tight junction organization
    term:
      id: GO:0120193
      label: tight junction organization
    modifier: DECREASED
  - preferred_term: Adherens junction organization
    term:
      id: GO:0034332
      label: adherens junction organization
    modifier: DECREASED
  cellular_components:
  - preferred_term: Cell-cell junction
    term:
      id: GO:0005911
      label: cell-cell junction
    modifier: DECREASED
  downstream:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    causal_link_type: DIRECT
    description: >-
      A failed barrier passes protein-rich fluid and red cells into the
      interstitium and airspace.
    evidence:
    - reference: PMID:41786071
      reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier
        dysfunction in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: As expected, hypoxia caused an increase in lung water content, lung injury scores, and inflammatory
        cytokine release, as well as a decrease in blood-gas barrier-related proteins.
      explanation: Couples loss of blood-gas barrier proteins to measured lung water accumulation under
        hypoxia in the canine HAPE model.
  - target: Secondary Inflammatory Amplification
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Barrier failure exposes the airspace to plasma constituents and cell
      debris, recruiting an inflammatory response that follows rather than
      precedes the lesion.
    evidence:
    - reference: PMID:40752453
      reference_title: Elevated cytokine levels in patients with High-altitude pulmonary edema.
      supports: SUPPORT
      directness: INDIRECT
      evidence_source: HUMAN_CLINICAL
      snippet: Our findings revealed significantly higher concentrations of IL-2, IL-10, and tumor necrosis
        factor (TNF) in the peripheral blood of HAPE patients when contrasted with those of healthy individuals
        (P < 0.001).
      explanation: Documents the inflammatory response present in established HAPE; graded INDIRECT because
        a cross-sectional comparison in established disease cannot establish that inflammation is downstream
        rather than upstream.
  evidence:
  - reference: PMID:11319198
    reference_title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pulmonary transcapillary escape of radiolabeled transferrin increased slightly from low
      to high altitude in the HAPE-susceptible subjects but remained within the limits of normal and did
      not differ significantly from the control subjects.
    explanation: Normal transcapillary protein escape at a stage when capillary pressure is already elevated
      is the key negative result placing barrier failure downstream of pressure, not as a primary defect.

- name: Impaired Alveolar Fluid Clearance
  description: >-
    Hypoxia downregulates the amiloride-sensitive epithelial sodium channel and
    Na+/K+-ATPase-driven transepithelial sodium transport that normally drives
    water out of the airspace. Reduced clearance does not by itself cause HAPE
    but determines how much fluid accumulates once the barrier has failed, and
    it is the rationale for beta-agonist prophylaxis. Its contribution is
    secondary to the hemodynamic lesion: in the tadalafil and dexamethasone
    prophylaxis trial, both drugs prevented HAPE while producing no measurable
    change in nasal potential difference, the surrogate for alveolar sodium
    transport.
  role: modifier
  biological_scale: TISSUE
  locations:
  - 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
  biological_processes:
  - preferred_term: Sodium ion transmembrane transport
    term:
      id: GO:0035725
      label: sodium ion transmembrane transport
    modifier: DECREASED
  downstream:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    causal_link_type: DIRECT
    description: >-
      Reduced active sodium and water reabsorption slows resolution of alveolar
      fluid, deepening the flooding produced by the barrier lesion.
    evidence:
    - reference: PMID:17015867
      reference_title: "Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary
        edema: a randomized trial."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: High-altitude pulmonary edema (HAPE) is caused by exaggerated hypoxic pulmonary vasoconstriction
        associated with decreased bioavailability of nitric oxide in the lungs and by impaired reabsorption
        of alveolar fluid.
      explanation: Names impaired alveolar fluid reabsorption as a co-contributor alongside the vascular
        lesion.
  evidence:
  - reference: PMID:17015867
    reference_title: "Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary
      edema: a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: No statistically significant difference between groups was found in change in nasal potentials
      and expression of leukocyte sodium transport protein messenger RNA.
    explanation: Effective prophylaxis without any measurable change in the sodium-transport surrogate
      supports treating impaired clearance as a modifier rather than the primary lesion; PARTIAL because
      a null result in a 29-subject trial is weak evidence.

- name: Secondary Inflammatory Amplification
  description: >-
    Once the barrier has failed, plasma proteins, cell-free DNA, and debris in
    the airspace recruit neutrophils and raise circulating cytokines. This
    amplifies injury and impairs resolution, but it is a consequence of the
    mechanical lesion, not its cause — the distinction that separates HAPE from
    ARDS and explains why anti-inflammatory prophylaxis is not the mainstay.
    Dexamethasone is the partial exception, and its prophylactic benefit tracks
    with pulmonary artery pressure reduction rather than with an anti-inflammatory
    effect.
  role: amplifier
  biological_scale: TISSUE
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  biological_processes:
  - preferred_term: Inflammatory response
    term:
      id: GO:0006954
      label: inflammatory response
    modifier: INCREASED
  - preferred_term: Leukocyte migration
    term:
      id: GO:0050900
      label: leukocyte migration
    modifier: INCREASED
  downstream:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    description: >-
      Inflammatory mediators further increase permeability and impede clearance,
      worsening flooding already initiated mechanically.
    evidence:
    - reference: PMID:41786071
      reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier
        dysfunction in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: Treatment with PFC could inhibit the inflammatory response and alleviate blood-gas barrier
        disruption in our canine and lung-on-chip models.
      explanation: An intervention that suppresses the inflammatory response also relieves barrier
        disruption, supporting inflammation as an amplifier of the barrier lesion.
  evidence:
  - reference: PMID:40752453
    reference_title: Elevated cytokine levels in patients with High-altitude pulmonary edema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Elevated IL-2, IL-10, and TNF in HAPE patients underscore immune dysregulation
      as a disease driver."
    explanation: Establishes measurable immune dysregulation in HAPE patients; the authors' framing as
      a driver is their interpretation of a cross-sectional comparison.

- name: High-Permeability Alveolar Flooding and Hypoxemia
  description: >-
    Protein-rich, often erythrocyte-containing fluid fills the interstitium and
    alveoli in a characteristically patchy distribution that mirrors the uneven
    perfusion that produced it. Flooded alveoli are perfused but not ventilated,
    creating shunt, and the resulting hypoxemia deepens alveolar hypoxia and so
    intensifies hypoxic vasoconstriction — a positive feedback loop that accounts
    for the rapid clinical deterioration and for why descent or oxygen, which
    break the loop at its origin, are so effective.
  role: consequence
  biological_scale: ORGANISM
  conforms_to: "alveolar_capillary_barrier_failure#Protein-Rich Alveolar Flooding and Gas-Exchange Failure"
  locations:
  - preferred_term: Alveolus of lung
    term:
      id: UBERON:0002299
      label: alveolus of lung
  - preferred_term: Lung
    term:
      id: UBERON:0002048
      label: lung
  biological_processes:
  - preferred_term: Respiratory gaseous exchange by respiratory system
    term:
      id: GO:0007585
      label: respiratory gaseous exchange by respiratory system
    modifier: DECREASED
  downstream:
  - target: Sustained Alveolar Hypoxia at Altitude
    causal_link_type: DIRECT
    description: >-
      Shunt-driven hypoxemia worsens alveolar hypoxia, closing a self-amplifying
      loop back onto the initiating trigger.
    evidence:
    - reference: PMID:1922223
      reference_title: Prevention of high-altitude pulmonary edema by nifedipine.
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: As compared with the subjects who received placebo, those who received nifedipine had a
        significantly lower mean (+/- SD) systolic pulmonary-artery pressure (41 +/- 8 vs. 53 +/- 16 mm
        Hg, P = 0.01), alveolar-arterial pressure gradient (6.6 +/- 3.8 vs. 11.8 +/- 4.4 mm Hg, P less
        than 0.001), and symptom score of acute mountain sickness (2.0 +/- 0.7 vs. 3.9 +/- 1.9, P less
        than 0.01) at 4559 m.
      explanation: Lowering pulmonary artery pressure improved the alveolar-arterial gradient, consistent
        with a pressure-driven gas-exchange loop; PARTIAL because the trial measures the intervention,
        not the feedback edge directly.
  evidence:
  - reference: PMID:39331568
    reference_title: Physiopathology of high-altitude pulmonary edema.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: A model is also presented to characterize HAPE nonsusceptible versus susceptible individuals
      based on the efficiency of alveolar-capillary oxygen uptake and estimated morphology of the air-blood
      barrier.
    explanation: Frames the clinical outcome in terms of alveolar-capillary oxygen uptake efficiency,
      the gas-exchange endpoint this node describes.

phenotypes:
- category: Respiratory
  name: Pulmonary Edema
  description: >-
    Non-cardiogenic, high-permeability pulmonary edema, patchy on imaging,
    developing 2-4 days after arrival at altitude.
  phenotype_term:
    preferred_term: Pulmonary edema
    term:
      id: HP:0100598
      label: Pulmonary edema
    temporality: ACUTE
  frequency: OBLIGATE
  evidence:
  - reference: PMID:11319198
    reference_title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "BACKGROUND: High-altitude pulmonary edema (HAPE) is characterized by severe pulmonary hypertension
      and bronchoalveolar lavage fluid changes indicative of inflammation."
    explanation: Confirms pulmonary edema as the defining feature of the syndrome.
- category: Respiratory
  name: Exertional Dyspnea
  description: >-
    Disproportionate breathlessness on exertion is characteristically the
    earliest symptom, preceding dyspnea at rest.
  phenotype_term:
    preferred_term: Exertional dyspnea
    term:
      id: HP:0002875
      label: Exertional dyspnea
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40938265
    reference_title: "High Altitude Pulmonary Edema Response to Continuous Airway Positive Pressure: A Randomized Controlled Trial: The HAPER CAPER Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sixty-four dyspneic adults with maximum oxygen saturation < 85%, recent arrival at high altitude,
      and noncardiogenic pulmonary edema on chest radiography were randomized to receive CPAP treatment
      plus usual care or usual care (oxygen-only) delivered through a sham CPAP mask.
    explanation: The trial's enrolment criteria establish dyspnea as a defining presenting feature of
      HAPE.
- category: Respiratory
  name: Hypoxemia
  description: >-
    Arterial oxygen saturation falls well below the value expected for the
    altitude, and the degree of desaturation grades severity.
  phenotype_term:
    preferred_term: Hypoxemia
    term:
      id: HP:0012418
      label: Hypoxemia
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:40938265
    reference_title: "High Altitude Pulmonary Edema Response to Continuous Airway Positive Pressure: A Randomized Controlled Trial: The HAPER CAPER Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Sixty-four dyspneic adults with maximum oxygen saturation < 85%, recent arrival at high altitude,
      and noncardiogenic pulmonary edema on chest radiography were randomized to receive CPAP treatment
      plus usual care or usual care (oxygen-only) delivered through a sham CPAP mask.
    explanation: An oxygen saturation below 85% was the enrolment threshold, documenting severe hypoxemia
      as a defining clinical feature.
- category: Cardiovascular
  name: Pulmonary Arterial Hypertension
  description: >-
    Precapillary pulmonary hypertension driven by hypoxic vasoconstriction, with
    a normal left atrial pressure. It precedes the edema rather than following
    it.
  phenotype_term:
    preferred_term: Pulmonary arterial hypertension
    term:
      id: HP:0002092
      label: Pulmonary arterial hypertension
    temporality: ACUTE
  frequency: VERY_FREQUENT
  evidence:
  - reference: PMID:1922223
    reference_title: Prevention of high-altitude pulmonary edema by nifedipine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: The prophylactic administration of nifedipine is effective in lowering pulmonary-artery
      pressure and preventing high-altitude pulmonary edema in susceptible subjects."
    explanation: Elevated pulmonary artery pressure is the treatment target in HAPE, establishing it as
      a cardinal feature.
- category: Respiratory
  name: Cough
  description: >-
    Initially dry and exertional, later productive of frothy and sometimes
    blood-tinged sputum as protein- and erythrocyte-rich fluid reaches the
    airways. Reported in 53.8 percent of the 411-patient Qinghai inpatient
    cohort (PMID:41316096, Table 1), which is the basis for the FREQUENT
    frequency assigned here.
  phenotype_term:
    preferred_term: Cough
    term:
      id: HP:0012735
      label: Cough
  frequency: FREQUENT
  evidence:
  - reference: PMID:41316096
    reference_title: "Clinical characteristic and prognosis of adult inpatients with high altitude pulmonary edema: a multi-central, retrospective study in plateau of China from 2012 to 2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: High-altitude pulmonary edema (HAPE) is characterized by loss of stamina, dyspnea, and dry
      cough during exertion, followed by dyspnea at rest, rales, cyanosis, cough, and pink, frothy sputum
    explanation: Describes the characteristic progression from dry exertional cough to productive cough
      with pink frothy sputum, which is the phenotype this entry records.
  - reference: PMID:41316096
    reference_title: "Clinical characteristic and prognosis of adult inpatients with high altitude pulmonary edema: a multi-central, retrospective study in plateau of China from 2012 to 2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Early symptoms include excessive exertional dyspnoea in relation to the patient\u2019s companions,
      mild cough, chest tightness and reduced exercise performance."
    explanation: Establishes that cough is present from the early stage as a mild, exertional symptom,
      before the productive phase the first quote describes.
- category: Cardiovascular
  name: Tachycardia
  description: Resting tachycardia accompanying hypoxemia and increased sympathetic drive.
  phenotype_term:
    preferred_term: Tachycardia
    term:
      id: HP:0001649
      label: Tachycardia
  frequency: FREQUENT
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: concurrent with at least two physical signs, including inspiratory crackles, central cyanosis,
      tachypnea, or tachycardia
    explanation: Tachycardia is one of the physical signs the clinical diagnostic criteria for HAPE draw
      on, establishing it as a recognised feature rather than an incidental finding.
  - reference: PMID:41316096
    reference_title: "Clinical characteristic and prognosis of adult inpatients with high altitude pulmonary edema: a multi-central, retrospective study in plateau of China from 2012 to 2022."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "physical examination: central cyanosis, shortness of breath, tachycardia, decreased breath
      sounds, and audible wet rales in the lungs during the stage of alveolar edema"
    explanation: Lists tachycardia among the examination findings in the diagnostic criteria used by this
      411-patient cohort.

prevalence:
- population: Global travellers to high altitude
  measure_type: PERIOD_PREVALENCE
  prevalence_class: UNKNOWN
  notes: >-
    Reported incidence spans three orders of magnitude because it is conditioned
    on ascent rate, individual susceptibility, and the altitude reached rather
    than on a fixed denominator population. Recorded as a range rather than a
    point estimate for that reason.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The reported incidence of HAPE varies widely across the global population, ranging from
      less than 0.01% to as high as 31%, depending on the rate of ascent, individual susceptibility, and
      the final altitude achieved
    explanation: Gives the reported incidence range and names the three determinants that make a single
      population figure meaningless for this disease.
- population: Trekkers and mountaineers ascending faster than 600 m per day in the Himalayas and Alps
  measure_type: PERIOD_PREVALENCE
  prevalence_class: ABOVE_1_IN_1000
  rate_per_100000: 4000.0
  notes: >-
    Approximately 4 percent in a defined rapid-ascent population. This is the
    figure to use when a denominator is needed, because unlike the global range
    it is conditioned on a stated ascent rate.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Among trekkers and mountaineers in the Himalayas and Alps who ascend at a rate exceeding
      600 m per day, the incidence of HAPE is approximately 4%.
    explanation: A rate-conditioned incidence estimate in a defined at-risk population.

diagnosis:
- name: Clinical diagnosis of HAPE
  description: >-
    HAPE is a clinical diagnosis; there is no gold-standard test. It requires
    recent rapid ascent above roughly 2,500-3,000 m within one to five days, a
    qualifying combination of symptoms and physical signs, radiographic
    non-cardiogenic pulmonary oedema, exclusion of ARDS, cardiogenic oedema and
    severe pneumonia, and improvement on descent or oxygen. The symptom-plus-sign
    threshold is what separates it from ordinary altitude breathlessness.
  presence: PRESENT
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A clinical diagnosis of HAPE requires the presence of a minimum of two symptoms, such as
      dyspnea at rest, cough, weakness, reduced exertional tolerance, or chest tightness, concurrent with
      at least two physical signs, including inspiratory crackles, central cyanosis, tachypnea, or tachycardia
    explanation: States the two-symptom plus two-sign threshold that defines the clinical diagnosis.
  notes: >-
    The five-point criteria used by the 411-patient Qinghai inpatient cohort
    (PMID:41316096) add the recent-ascent window, chest CT or radiograph
    findings, exclusion of ARDS, cardiogenic pulmonary oedema and severe
    pneumonia, and symptom remission on transfer to low altitude.

has_subtypes:
- name: Classic HAPE
  display_name: Classic (lowlander ascent) HAPE
  description: >-
    The common form, affecting non-acclimatised lowlanders after rapid ascent
    above 2,500-3,000 m. This is the presentation the pathophysiology and
    treatment sections describe by default.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The first and most common form affects non-acclimatized lowlanders following a rapid ascent
      above 2500\u20133000 m."
    explanation: Defines the common lowlander-ascent form as one of two recognised onset patterns.
- name: Re-entry HAPE
  display_name: Re-entry HAPE (highland dwellers returning to altitude)
  description: >-
    Occurs in highland residents who descend to low altitude and then reascend.
    The at-risk population is the inverse of the classic form - people
    acclimatised by residence who have lost that acclimatisation - which is what
    makes it worth separating, since it changes who should be counselled about
    prophylaxis. The mechanism is regarded as the same, so this is a variant of
    population and presentation rather than of pathophysiology.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The second form, referred to as re-entry HAPE, is observed in highland dwellers who reascend
      after a period of time at sea level.
    explanation: Defines re-entry HAPE and its distinct at-risk population.
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: The pathophysiological mechanism is likely identical for both types
    explanation: Supports treating re-entry HAPE as a population variant rather than a mechanistically
      distinct disease; the authors' hedge is preserved.

genetic:
- name: JAK2
  gene_term:
    preferred_term: JAK2
    term:
      id: hgnc:6192
      label: JAK2
  relationship_type: SUSCEPTIBILITY
  presence: PRESENT
  notes: >-
    Reported among the genetic predispositions to HAPE. Susceptibility, not
    causation - HAPE requires the altitude exposure, and no single locus is
    necessary or sufficient.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A genetic predisposition is also recognized, linked to specific mutations such as those in
      the JAK2 gene, P1B1 cytochrome genes, and a deletion in the histidine-rich glycoprotein gene, the
      latter of which is associated with an earlier onset of the condition
    explanation: Names JAK2 among recognised predisposing loci; graded PARTIAL because the case series
      cites this secondarily rather than reporting a primary association study.
- name: HRG
  gene_term:
    preferred_term: HRG
    term:
      id: hgnc:5181
      label: HRG
  relationship_type: SUSCEPTIBILITY
  presence: PRESENT
  notes: >-
    A deletion in the histidine-rich glycoprotein gene is reported to associate
    with earlier onset, making this the one named locus carrying a stated
    phenotypic correlate rather than bare susceptibility.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: a deletion in the histidine-rich glycoprotein gene, the latter of which is associated with
      an earlier onset of the condition
    explanation: Reports the HRG deletion and its association with earlier onset; PARTIAL for the same
      secondary-citation reason.
- name: Unidentified cytochrome P450 locus
  relationship_type: SUSCEPTIBILITY
  presence: PRESENT
  notes: >-
    Deliberately left unbound. PMID:42254115 prints the symbol as "P1B1
    cytochrome genes", which is not a valid HGNC symbol, and the primary
    references behind that sentence were not consulted. An earlier draft of this
    entry expanded it to CYP1B1 and bound hgnc:2597; that binding was withdrawn
    because a PubMed check returns no papers linking CYP1B1 to high altitude
    pulmonary edema, while CYP11B2 (aldosterone synthase) returns several and
    CYP17A1 one. The most likely reading is therefore CYP11B2, but reading
    "P1B1" as "11B2" is an inference this citation does not license, and
    substituting one guess for another would be no better than the first. The
    free-text name records that a cytochrome P450 locus is claimed; the gene
    identity is left open until the primary sources are read.
  evidence:
  - reference: PMID:42254115
    reference_title: "High-altitude pulmonary edema: a case series of four patients from Nepal."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: A genetic predisposition is also recognized, linked to specific mutations such as those in
      the JAK2 gene, P1B1 cytochrome genes, and a deletion in the histidine-rich glycoprotein gene
    explanation: Names the cytochrome locus among recognised predispositions; PARTIAL because the symbol
      is printed non-canonically and the citation is secondary.

environmental:
- name: Rapid Ascent to High Altitude
  description: >-
    Ascent above roughly 2,500-3,000 m, particularly when rapid and combined
    with exertion, is the necessary environmental exposure - necessary but not
    sufficient, since HAPE strikes only a susceptible minority of those who
    ascend, which is what the susceptibility loci and the vasoreactivity
    knowledge gap are about. Rate
    of ascent, absolute altitude attained, sleeping altitude, and exertion during
    ascent are each independent determinants of risk, which is why staged ascent
    and preacclimatization are effective prevention.
  exposure_term:
    preferred_term: exposure to hypobaric hypoxia during ascent to high altitude
  presence: PRESENT
  effect: HARMFUL
  notes: >-
    Deliberately left unbound. ECTO and XCO were both searched (2026-08) for a
    high-altitude or hypobaric-hypoxia exposure class and neither has one. The
    closest XCO candidates are experimental apparatus and condition terms
    (XCO:0001406 hypobaric chamber, XCO:0000010 controlled air oxygen content)
    that describe a laboratory manipulation rather than the natural environmental
    exposure a traveller undergoes, so binding one would misdescribe the
    exposure. Revisit if ECTO adds an altitude exposure class.
  influences_mechanisms:
  - target: Sustained Alveolar Hypoxia at Altitude
    environmental_effect: TRIGGERS
    causal_link_type: DIRECT
    description: >-
      The fall in barometric pressure on ascent is what lowers alveolar oxygen
      tension; the exposure and the trigger node are the same physical event.
    evidence:
    - reference: PMID:39331568
      reference_title: Physiopathology of high-altitude pulmonary edema.
      supports: SUPPORT
      evidence_source: OTHER
      snippet: Exposure to hypobaric hypoxia, especially when associated with exercise, is a condition
        potentially leading to the development of the so-called high-altitude pulmonary edema (HAPE).
      explanation: Directly ties the hypobaric hypoxia exposure to HAPE development.
  evidence:
  - reference: PMID:38682380
    reference_title: Evaluation and Management of the Individual with Recurrent High Altitude Pulmonary Edema.
    supports: SUPPORT
    evidence_source: OTHER
    snippet: a multipronged approach including pharmacologic prophylaxis, careful planning about the rate
      of ascent, and the degree of physical effort and other strategies, such as preacclimatization, staged
      ascent, and use of hypoxic tents, can be employed to reduce the risk of recurrence with future travel
    explanation: That modifying rate of ascent, exertion, and acclimatization reduces recurrence risk
      establishes these exposure parameters as causal determinants.

treatments:
- name: Descent and Supplemental Oxygen
  description: >-
    Immediate descent is the definitive treatment and reverses the disease by
    removing the hypoxic stimulus. Where descent is impossible, supplemental
    oxygen, and portable hyperbaric therapy where available, substitute for it.
    Both act at the top of the causal chain rather than on the edema itself.
  therapeutic_modality: OTHER
  treatment_term:
    preferred_term: Oxygen Therapy
    term:
      id: NCIT:C94624
      label: Oxygen Therapy
  target_mechanisms:
  - target: Sustained Alveolar Hypoxia at Altitude
    treatment_effect: INHIBITS
    description: >-
      Raising inspired oxygen tension abolishes the hypoxic stimulus for
      pulmonary vasoconstriction and breaks the hypoxemia feedback loop.
  evidence:
  - reference: PMID:40938265
    reference_title: "High Altitude Pulmonary Edema Response to Continuous Airway Positive Pressure: A Randomized Controlled Trial: The HAPER CAPER Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSION: Both CPAP with high-flow oxygen and high-flow oxygen alone are highly effective
      for the treatment of HAPE."
    explanation: A randomized trial establishing high-flow oxygen alone as highly effective treatment.
- name: Continuous Positive Airway Pressure
  description: >-
    CPAP added to high-flow oxygen was tested in a randomized trial against sham
    CPAP with high-flow oxygen. It did not accelerate resolution beyond oxygen
    alone, so it is not an established addition where oxygen is available; the
    trial is recorded here because the negative result is the clinically useful
    finding.
  therapeutic_modality: DEVICE
  treatment_term:
    preferred_term: Continuous Positive Airway Pressure
    term:
      id: NCIT:C124040
      label: Continuous Positive Airway Pressure
  target_mechanisms:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    treatment_effect: INHIBITS
    description: >-
      Positive airway pressure recruits flooded alveoli and reduces shunt,
      acting on the gas-exchange consequence rather than the vascular cause.
  evidence:
  - reference: PMID:40938265
    reference_title: "High Altitude Pulmonary Edema Response to Continuous Airway Positive Pressure: A Randomized Controlled Trial: The HAPER CAPER Trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "RESULTS: HAPE resolution in the CPAP plus high FiO2 group and the high flow oxygen alone
      group was similar."
    explanation: The trial found no advantage of adding CPAP to high-flow oxygen; PARTIAL records an
      effective but not additive intervention.
- name: Nifedipine Prophylaxis
  description: >-
    A dihydropyridine calcium channel blocker that lowers pulmonary artery
    pressure. In susceptible mountaineers ascending rapidly to 4,559 m it cut
    HAPE incidence from 7 of 11 on placebo to 1 of 10. It remains the standard
    pharmacologic prophylaxis for individuals with a HAPE history.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: nifedipine
      term:
        id: CHEBI:7565
        label: nifedipine
  target_mechanisms:
  - target: Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
    treatment_effect: INHIBITS
    description: >-
      Calcium channel blockade relaxes pulmonary arterial smooth muscle,
      lowering the pressure that drives capillary stress failure.
  evidence:
  - reference: PMID:1922223
    reference_title: Prevention of high-altitude pulmonary edema by nifedipine.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: Seven of the 11 subjects who received placebo but only 1 of the 10 subjects who received
      nifedipine had pulmonary edema at 4559 m (P = 0.01).
    explanation: A randomized placebo-controlled result directly demonstrating prophylactic efficacy.
- name: Tadalafil Prophylaxis
  description: >-
    A phosphodiesterase-5 inhibitor that potentiates nitric-oxide-mediated
    pulmonary vasodilation, addressing the reduced nitric oxide bioavailability
    that underlies exaggerated hypoxic vasoconstriction. An alternative to
    nifedipine in susceptible individuals.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: tadalafil
      term:
        id: CHEBI:71940
        label: tadalafil
  target_mechanisms:
  - target: Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
    treatment_effect: INHIBITS
    description: >-
      PDE5 inhibition raises cGMP in pulmonary vascular smooth muscle, opposing
      hypoxic vasoconstriction.
  evidence:
  - reference: PMID:17015867
    reference_title: "Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary
      edema: a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: High-altitude pulmonary edema developed in 7 of 9 participants receiving placebo and 1 of
      the remaining 8 participants receiving tadalafil but in none of the 10 participants receiving dexamethasone
      (P = 0.007 for tadalafil vs. placebo; P < 0.001 for dexamethasone vs. placebo).
    explanation: Randomized evidence of prophylactic efficacy for both tadalafil and dexamethasone.
- name: Dexamethasone Prophylaxis
  description: >-
    A glucocorticoid that prevented HAPE outright in the same randomized trial
    and also lowered systolic pulmonary artery pressure. Notably its benefit
    tracked with the hemodynamic effect and not with any measurable change in
    alveolar sodium transport, which is part of why the pressure mechanism is
    considered primary.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: dexamethasone
      term:
        id: CHEBI:41879
        label: dexamethasone
  target_mechanisms:
  - target: Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
    treatment_effect: INHIBITS
    description: >-
      Reduces the rise in systolic pulmonary artery pressure on ascent.
  evidence:
  - reference: PMID:17015867
    reference_title: "Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary
      edema: a randomized trial."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSIONS: Both dexamethasone and tadalafil decrease systolic pulmonary artery pressure
      and may reduce the incidence of HAPE in adults with a history of HAPE."
    explanation: The trial's conclusion ties the prophylactic benefit to a reduction in systolic pulmonary
      artery pressure, the proposed mechanism.
- name: Furosemide
  description: >-
    A loop diuretic used adjunctively in some centres. A retrospective cohort of
    273 HAPE inpatients found lower CT severity scores with furosemide, but the
    evidence is observational and its effect on outcome is unestablished; it is
    not a substitute for descent or oxygen.
  therapeutic_modality: SMALL_MOLECULE
  treatment_term:
    preferred_term: Pharmacotherapy
    term:
      id: NCIT:C15986
      label: Pharmacotherapy
    therapeutic_agent:
    - preferred_term: furosemide
      term:
        id: CHEBI:47426
        label: furosemide
  target_mechanisms:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    treatment_effect: INHIBITS
    description: >-
      Diuresis reduces pulmonary vascular filling pressure and total lung water,
      acting on the accumulated edema rather than its cause.
  evidence:
  - reference: PMID:38438895
    reference_title: Effect of furosemide in the treatment of high-altitude pulmonary edema.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "CONCLUSION: Furosemide helps alleviate pulmonary edema in HAPE patients, but further research
      is needed to clarify its impact on prognosis."
    explanation: A retrospective cohort supporting radiographic benefit while explicitly leaving prognosis
      unresolved; PARTIAL reflects the authors' own hedge.

experimental_models:
- name: Hypoxia-exposed lung-on-chip model of blood-gas barrier dysfunction
  description: >-
    A microfluidic lung-on-chip exposed to 3% oxygen for 24 hours to recapitulate
    hypoxic lung injury at the organ level, used alongside a canine HAPE model to
    test perfluorocarbon and to localize its effect to the HIF-1-alpha/HO-1
    pathway. The chip isolates the direct effect of hypoxia on the barrier from
    the hemodynamic overperfusion that drives HAPE in vivo, which is both what
    makes it informative and what bounds it.
  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
  conditions:
  - hypoxia (3% oxygen, 24 h)
  - perfluorocarbon co-culture (10%)
  culture_system: Microfluidic lung-on-chip under hypoxic gas control
  publication: PMID:41786071
  modeled_mechanisms:
  - target: Capillary Stress Failure of the Blood-Gas Barrier
    relationship: PARTIALLY_RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces hypoxia-driven loss of blood-gas barrier proteins and its
      pharmacological reversal.
    limitations: >-
      The chip applies hypoxia directly to the barrier and has no pulmonary
      circulation, so it cannot reproduce the exaggerated, spatially uneven
      hypoxic vasoconstriction and capillary overperfusion that are the actual
      initiating lesion in HAPE. It therefore models the downstream barrier
      consequence of hypoxia, not the hemodynamic cause.
    readouts:
    - name: Blood-gas barrier-related protein expression
      target: Capillary Stress Failure of the Blood-Gas Barrier
      direction: DECREASED
      interpretation: >-
        Loss of barrier proteins under hypoxia is the molecular correlate of the
        barrier-failure node.
      evidence:
      - reference: PMID:41786071
        reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier
          dysfunction in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
        supports: SUPPORT
        evidence_source: IN_VITRO
        snippet: Then, the latter model was exposed to hypoxia (3% oxygen; 24 h) and co-cultured with
          10% PFC.
        explanation: Documents the hypoxic exposure protocol under which the barrier readout was
          measured.
    evidence:
    - reference: PMID:41786071
      reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier
        dysfunction in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Next, we created a lung-on-chip model that allowed lung injury to be recapitulated in
        vitro at the organ level."
      explanation: Establishes the chip as an organ-level model of the hypoxic lung injury this node
        describes.
  evidence:
  - reference: PMID:41786071
    reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier dysfunction
      in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "In addition, we found that PFC blocked activation of the hypoxia-inducible factor-1α (HIF-1α)/heme
      oxygenase-1 (HO-1) signaling pathway."
    explanation: The chip localized the therapeutic effect to a specific signaling pathway, supporting
      its inclusion as a mechanistically informative model.

animal_models:
- name: Canine hypobaric HAPE model (simulated 6000 m)
  species: Dog
  description: >-
    Beagles exposed to a simulated altitude of 6,000 m for 48 hours develop
    increased lung water content, raised lung injury scores, inflammatory
    cytokine release, and loss of blood-gas barrier proteins. Used as the in vivo
    arm of the perfluorocarbon study.
  publication: PMID:41786071
  modeled_mechanisms:
  - target: High-Permeability Alveolar Flooding and Hypoxemia
    relationship: RECAPITULATES
    fidelity: MODERATE
    description: >-
      Reproduces the hypobaric-hypoxia-induced accumulation of extravascular
      lung water that defines the human syndrome.
    limitations: >-
      A 48-hour exposure to a simulated 6,000 m in an anesthetized large-animal
      preparation compresses a clinical course that in humans unfolds over two to
      four days of active ascent, and the model does not select for the
      individual hypoxic vasoreactivity that determines human susceptibility.
    readouts:
    - name: Lung water content and lung injury score
      target: High-Permeability Alveolar Flooding and Hypoxemia
      direction: INCREASED
      interpretation: >-
        Direct measurement of the alveolar flooding endpoint under hypobaric
        hypoxia.
      evidence:
      - reference: PMID:41786071
        reference_title: Perfluorocarbon ameliorates high-altitude pulmonary edema and blood-gas barrier
          dysfunction in a canine model and a lung-on-chip model by suppressing the HIF-1α/HO-1 pathway.
        supports: SUPPORT
        evidence_source: MODEL_ORGANISM
        snippet: We exposed beagle dogs to a simulated altitude of 6000 m for 48 h to establish the HAPE
          model and treated them with vaporized PFC.
        explanation: Documents the exposure protocol establishing the canine HAPE model.

mechanistic_hypotheses:
- hypothesis_group_id: pressure_primary_model
  hypothesis_label: Capillary stress failure is the primary lesion, inflammation secondary
  status: CANONICAL
  description: >-
    HAPE begins as a hemodynamic disease: exaggerated, uneven hypoxic
    vasoconstriction raises pulmonary capillary pressure past the mechanical
    tolerance of the blood-gas barrier, and inflammation follows the resulting
    stress failure. The decisive evidence is that transcapillary protein escape
    is still normal in susceptible subjects whose capillary pressure has already
    risen, and that agents which lower pulmonary artery pressure prevent the
    disease while anti-inflammatory action alone does not account for the benefit.
- hypothesis_group_id: inflammation_primary_model
  hypothesis_label: Inflammation contributes to initiation rather than only amplifying
  status: ALTERNATIVE
  description: >-
    A minority view holds that immune dysregulation contributes to the initiation
    of barrier failure rather than merely amplifying it, supported by elevated
    IL-2, IL-10, and TNF in HAPE patients and by cytokine profiles that
    discriminate cases from acclimatized controls with high accuracy. The
    unresolved problem is temporal: the human cytokine data are cross-sectional
    in established disease and cannot separate cause from consequence, and
    lavage inflammation appears after the pressure rise in the studies that
    measured both.

discussions:
- discussion_id: hape_susceptibility_vasoreactivity_basis
  kind: KNOWLEDGE_GAP
  prompt: >-
    Does the individual variation in hypoxic pulmonary vasoreactivity that
    determines HAPE susceptibility have a tractable molecular basis, and can it
    be measured at low altitude to predict risk before travel?
  attaches_to:
  - pathophysiology#Exaggerated and Uneven Hypoxic Pulmonary Vasoconstriction
  rationale: >-
    Susceptibility is reproducible within individuals and is the single largest
    determinant of who develops HAPE, yet prophylaxis is currently offered on the
    basis of prior episodes rather than any prospective measurement. Enhanced
    hypoxic vasoreactivity is already detectable at low altitude in susceptible
    subjects, so a predictive test is physiologically plausible; what is missing
    is a validated threshold and an understanding of what sets the reactivity.
- discussion_id: hape_chip_lacks_hemodynamic_initiation
  kind: HUMAN_MODEL_MISMATCH
  prompt: >-
    Can a lung-on-chip that applies hypoxia directly to the alveolar barrier be
    treated as a model of HAPE, when the human disease is initiated by capillary
    overperfusion rather than by hypoxia acting on the barrier?
  attaches_to:
  - experimental_models#Hypoxia-exposed lung-on-chip model of blood-gas barrier dysfunction
  - pathophysiology#Capillary Stress Failure of the Blood-Gas Barrier
  rationale: >-
    The chip reproduces hypoxia-driven barrier protein loss and responds to
    perfluorocarbon, but it has no pulmonary circulation and therefore cannot
    generate the uneven vasoconstriction and regional capillary hypertension that
    the human evidence identifies as the initiating lesion. The mismatch matters
    because a therapeutic that works by protecting the barrier against direct
    hypoxic injury need not work against a mechanically overloaded barrier. A
    chip incorporating controllable perfusion pressure across a capillary network
    would test whether the same protection holds when the insult is hemodynamic.

references:
- reference: PMID:37833187
  title: "Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment
    of Acute Altitude Illness: 2024 Update."
- reference: PMID:39331568
  title: Physiopathology of high-altitude pulmonary edema.
- reference: PMID:38682380
  title: Evaluation and Management of the Individual with Recurrent High Altitude Pulmonary Edema.
- reference: PMID:11319198
  title: High-altitude pulmonary edema is initially caused by an increase in capillary pressure.
- reference: PMID:25539941
  title: "Physiology in Medicine: A physiologic approach to prevention and treatment of acute high-altitude
    illnesses."

📚

References & Deep Research

References

5

PMID:37833187

Wilderness Medical Society Clinical Practice Guidelines for the Prevention, Diagnosis, and Treatment of Acute Altitude Illness: 2024 Update.

No top-level findings curated for this source.

PMID:39331568

Physiopathology of high-altitude pulmonary edema.

No top-level findings curated for this source.

PMID:38682380

Evaluation and Management of the Individual with Recurrent High Altitude Pulmonary Edema.

No top-level findings curated for this source.

PMID:11319198

High-altitude pulmonary edema is initially caused by an increase in capillary pressure.

No top-level findings curated for this source.

PMID:25539941

Physiology in Medicine: A physiologic approach to prevention and treatment of acute high-altitude illnesses.

No top-level findings curated for this source.

High Altitude Pulmonary Edema

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