New Insights in the Pathogenesis of High-Altitude Pulmonary Edema

doi:10.1016/j.pcad.2010.02.004

Progress in Cardiovascular Diseases

Volume 52, Issue 6, May–June 2010, Pages 485-492

https://doi.org/10.1016/j.pcad.2010.02.004 Get rights and content

Abstract

High-altitude pulmonary edema is a life-threatening condition occurring in predisposed but otherwise healthy individuals. It therefore permits the study of underlying mechanisms of pulmonary edema in the absence of confounding factors such as coexisting cardiovascular or pulmonary disease, and/or drug therapy.

There is evidence that some degree of asymptomatic alveolar fluid accumulation may represent a normal phenomenon in healthy humans shortly after arrival at high altitude. Two fundamental mechanisms then determine whether this fluid accumulation is cleared or whether it progresses to HAPE: the quantity of liquid escaping from the pulmonary vasculature and the rate of its clearance by the alveolar respiratory epithelium. The former is directly related to the degree of hypoxia-induced pulmonary hypertension, whereas the latter is determined by the alveolar epithelial sodium transport. Here, we will review evidence that, in HAPE-prone subjects, impaired pulmonary endothelial and epithelial NO synthesis and/or bioavailability may represent a central underlying defect predisposing to exaggerated hypoxic pulmonary vasoconstriction and, in turn, capillary stress failure and alveolar fluid flooding. We will then demonstrate that exaggerated pulmonary hypertension, although possibly a conditio sine qua non, may not always be sufficient to induce HAPE and how defective alveolar fluid clearance may represent a second important pathogenic mechanism.

Section snippets

Exaggerated hypoxic pulmonary hypertension

Exaggerated pulmonary hypertension is a hallmark of HAPE,4, 5 and several observations indicate that it contributes to its pathogenesis. Anatomical (congenital absence of the right pulmonary artery, pulmonary artery occlusion from granulomatous mediastinitis)6, 7 or functional (Down syndrome)8, 9 abnormalities that facilitate pulmonary hypertension are risk factors for developing HAPE at relatively low altitude (1500-2500 m). Lowering of pulmonary artery pressure with pharmacologic agents of

Conclusion

Based on our results, we suggest the following new concept for the pathogenesis of HAPE (Fig 5). Pulmonary edema results from a persistent imbalance between the forces that drive water into the airspace and the biologic mechanisms for its removal. In HAPE-prone subjects, alveolar fluid flooding is augmented because of exaggerated pulmonary hypertension that appears to be related, at least in part, to defective NO synthesis leading to endothelial dysfunction and exaggerated sympathetic

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

Acknowledgments

The authors' research was supported by grants from the Swiss National Science Foundation, the Dr Max Cloëtta Foundation, the Novartis Foundation, the Eagle Foundation, the Leenaards Foundation, and the Placide Nicod Foundation.

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High altitude pulmonary edema (HAPE) is a high-altitude idiopathic disease with serious consequences due to hypoxia at high altitude, and there is individual genetic susceptibility. Whole-exome sequencing (WES) is an effective tool for studying the genetic etiology of HAPE and can identify potentially novel mutations that may cause protein instability and may contribute to the development of HAPE.
A total of 50 unrelated HAPE patients were examined using WES, and the available bioinformatics tools were used to perform an analysis of exonic regions. Using the Phenolyzer program, disease candidate gene analysis was carried out. SIFT, PolyPhen-2, Mutation Taster, CADD, DANN, and I-Mutant software were used to assess the effects of genetic variations on protein function.
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Citation Excerpt :
However, this body reaction eventually becomes maladaptive and causes serious clinical manifestations like high-altitude pulmonary edema or HAPE [1], a life-threatening condition caused by a rapid accumulation of extracellular fluid flooding in the pulmonary alveoli [1,3]. Yet the precise origin of HAPE has been attributed to an increase in intrapulmonary arterial pressure [4–7], the putative role of a direct or an indirect pathologic insult [8] has been neglected. The Andes is the region with the highest incidence of HAPE worldwide [9–11].
Exposure to hypoxic environments when ascending at high altitudes may cause life-threatening pulmonary edema (HAPE) due to a rapid accumulation of extracellular fluid flooding in the pulmonary alveoli. In Andeans, high-altitude adaptation occurs at the expense of being more prone to chronic mountain sickness: relative hypoventilation, excess pulmonary hypertension, and secondary polycythemia. Because HAPE prevalence is high in the Andes, we posit the hypothesis that a high hemoglobine mass may increase HAPE risk. In support of it, high intrapulmonary hypertension along with hyperviscosity produced by polycytemia may enhance sear forces and intravascular hemolysis, thus leading to increased acellular hemoglobin and the subsequent damage of the alveolar and endothelial barrier. It is proposed to investigate the relationship between the vaso-endothelial homeostasis and erythropoiesis in the maladaptation to high altitude and HAPE. This research is especially important when reentry HAPE, since rheologic properties of blood changes with rapid ascent to high altitudes.
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Male ICR mice were assigned to the normoxia group and several hypoxia groups, given sterile water, CA or dexamethasone orally, once daily for four consecutive days. One hour after the final gavage, mice in the above hypoxia groups were put into the normobaric hypoxia chamber (9.5% O₂) for 24 h while mice in normoxia group remained outside the chamber. After hypoxia exposure, lung water content (LWC), pulmonary vascular permeability, the protein content of bronchoalveolar lavage fluid (BALF), plasma total nitrate/nitrite (NO_x) and endothelin-1 (ET-1) content, histological and ultra-microstructure analyses were performed. Expression of occludin was assayed by immunohistochemistry.
In a hypoxic environment of 9.5% O₂, mice treated with 100 mg/kg body wt CA had significantly lower LWC and BALF protein content than mice in the hypoxia vehicle group. Meanwhile, mice in CA group showed intact lung blood-gas-barrier, increased levels of plasma total NO, decreased levels of plasma ET-1 and upregulation of occludin expression.
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Hypobaric hypoxia elicits several patho-physiological manifestations, some of which are known to be lethal. Among various molecular mechanisms proposed so far, perturbation in redox state due to imbalance between radical generation and antioxidant defence is promising. These molecular events are also related to hypoxic status of cancer cells and therefore its understanding has extended clinical advantage beyond high altitude hypoxia. In present study, however, the focus was to understand and propose a model for rapid acclimatization of high altitude visitors to enhance their performance based on molecular changes. We considered using simulated hypobaric hypoxia at some established thresholds of high altitude stratification based on known physiological effects. Previous studies have focused on the temporal aspect while overlooking the effects of varying pO₂ levels during exposure to hypobaric hypoxia. The pO₂ levels, indicative of altitude, are crucial to redox homeostasis and can be the limiting factor during acclimatization to hypobaric hypoxia. In this study we present the effects of acute (24 h) exposure to high (3049 m; pO₂: 71 kPa), very high (4573 m; pO₂: 59 kPa) and extreme altitude (7620 m; pO₂: 40 kPa) zones on lung and plasma using semi-quantitative redox specific transcripts and quantitative proteo-bioinformatics workflow in conjunction with redox stress assays. It was observed that direct exposure to extreme altitude caused 100% mortality, which turned into high survival rate after pre-exposure to 59 kPa, for which molecular explanation were also found. The pO₂ of 59 kPa (very high altitude zone) elicits systemic energy and redox homeostatic processes by modulating the STAT3-RXR-Nrf2 trio. Finally we posit the various processes downstream of STAT3-RXR-Nrf2 and the plasma proteins that can be used to ascertain the redox status of an individual.

View all citing articles on Scopus

: Statement of Conflict of Interest: see page 491.

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New Insights in the Pathogenesis of High-Altitude Pulmonary Edema

Abstract

Section snippets

Exaggerated hypoxic pulmonary hypertension

Conclusion

Statement of Conflict of Interest

Acknowledgments

Respir Physiol Neurobiol

Lancet

J Am Coll Cardiol

Pharmacol Ther

J Am Coll Cardiol

Lancet

Chest

Pulmonary edema

Physiol Rev

High-altitude pulmonary edema: from exaggerated pulmonary hypertension to a defect in transepithelial sodium transport

Adv Exp Med Biol

High-altitude pulmonary edema: current concepts

Ann Rev Med

Fatal high altitude pulmonary edema associated with absence of the left pulmonary artery

High Alt Med Biol

High-altitude pulmonary edema with absent right pulmonary artery

Pediatrics

Pulmonary edema in 6 children with Down syndrome during travel to moderate altitudes

Pediatrics

Pulmonary hypertension in high-altitude dwellers: novel mechanisms, unsuspected predisposing factors

Adv Exp Med Biol

The effect of vasodilatators on pulmonary hemodynamics in high-altitude pulmonary edema—a comparison

Int J Sports Med

Prevention of high-altitude pulmonary edema by nifedipine

N Engl J Med

Both tadalafil and dexamethasone may reduce the incidence of high-altitude pulmonary edema: a randomized trial

Ann Intern Med

Inhaled nitric oxide for high-altitude pulmonary edema

N Engl J Med

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

Circulation

Pulmonary vein contracts in response to hypoxia

Am J Physiol

Hypoxic vasoconstriction and fluid filtration in pig lungs

J Appl Physiol

Pathogenesis of high-altitude pulmonary edema: inflammation is not an etiologic factor

JAMA

Exhaled nitric oxide in high-altitude pulmonary edema: role in the regulation of pulmonary vascular tone and evidence for a role against inflammation

Am J Respir Crit Care Med

Inhaled nitric oxide: a selective pulmonary vasodilator reversing hypoxic pulmonary vasoconstriction

Circulation

eNOS allelic variants at the same locus associate with HAPE and adaptation

Thorax

Positive association of the endothelial nitric oxide synthase gene polymorphisms with high-altitude pulmonary edema

Circulation