Stress failure plays a major role in the development of high-altitude pulmonary oedema in rats

Abstract

Hypoxia and exertion are considered as the two main factors in the development of high-altitude pulmonary oedema (HAPE), however its pathophysiology remains unclear. Therefore, we established a model in which 32 Sprague-Dawley rats were randomly assigned to normoxic rest, hypoxic rest, normoxic exercise and hypoxic exercise.An altitude of 4,700 m was simulated using hypobaric hypoxia, while exercise consisted 48 h walk with 15-20 min breaks every 4 h. Arterial blood gas, bronchoalveolar lavage (BAL), lung wetto-dry weight (W/D) ratio and histological measurements were conducted on each animal.In rats exercising in hypoxia, BAL protein and lung W/D ratio were significantly increased but no changes in BAL leukotriene B 4 and immunoglobulin M were observed. In the same group, lung histology showed typical haemorrhagic lung oedema and disruption of both alveolar epithelium and capillary endothelium while hypoxia or exertion alone only induced slight endothelium and epithelium swelling/disruption.Our study established a direct link between histological and physiological evidence of HAPElike symptoms and we demonstrated that hypoxia and exertion can synergistically induce HAPElike symptoms in Sprague-Dawley rats without inducing lung inflammation. We therefore propose that alveolar epithelium and capillary endothelium stress failure play a major role in the development of HAPE.KEYWORDS: Exercise, high-altitude pulmonary oedema, hypobaric hypoxia, rat model, stress failure H igh-altitude pulmonary oedema (HAPE) is a potentially fatal condition that may affect nonacclimatised individuals who ascend rapidly to altitudes .3,000 m [1, 2]. Approximately 2% of individuals exposed to high altitude are affected severely enough by HAPE to seek treatment [3]. However, the incidence of sub-clinical HAPE may be as high as 75% in individuals travelling at an altitude .4,500 m [4].Hypoxia and exertion have been identified as the two main factors in HAPE development [5]. However, the exact mechanisms that trigger the development of HAPE are not completely understood. Although factors such as inflammation and decreased alveolar fluid clearance are thought to be important in HAPE pathophysiology [6][7][8][9], pulmonary capillary stress failure, which results from an uneven hypoxic pulmonary vascoconstriction [10,11], has been suggested to be the primary inciting mechanism. Indeed, increased pulmonary capillary transmural pressure [12][13][14] causes the rupture of the alveolocapillary membrane [15], allowing the flooding of the alveolar space with a protein rich and haemorrhagic oedema fluid. HOPKINS et al. [16] found evidence of stress failure in exercising humans under hypoxic conditions, and SWENSON et al. [17] showed the presence of red blood cells as well as increased protein concentration in BAL fluid from humans with HAPE, without significant changes in BAL cytokines. However, whether pulmonary capillary stress failure is the primary mechanism in the development of HAPE is not conclusive since direct evidence of capi...

High‐altitude Pulmonary Edema: Review

“…Rats exposed to physiologically relevant levels of hypobaric hypoxia developed elevated bronchoalveolar lavage (BAL) fluid total protein, albumin and red blood cell concentrations. These changes were more evident in animals subjected to higher levels of physical exercise under hypoxic conditions and were not observed in normoxic resting animals 31) .…”

“…The increasing pressure on the capillaries imparts excessive stress on the collagen and the extracellular matrix of the alveolar capillary barrier, which in turn leads to the mechanically induced breaks in the blood gas barrier, also described as the "stress failure" of pulmonary capillaries by West and colleagues (1991) 30) . A study using a rat model by Bai et al in 2010 showed a direct relation between the histological evidence of pulmonary capillary stress failure and progression of an illness similar to HAPE 31) . Rats exposed to physiologically relevant levels of hypobaric hypoxia developed elevated bronchoalveolar lavage (BAL) fluid total protein, albumin and red blood cell concentrations.…”

Periostin Deficiency Causes Severe and Lethal Lung Injury in Mice With Bleomycin Administration

“…7,33 Furthermore, under hypobaric hypoxia especially with exercise 49 and high-pressure ventilation, 50 the intact lungs are injured mechanically and exhibit rupture of the alveolocapillary membrane or a change in the pulmonary permeability. Digesting collagen greatly decreases stiffness, 51 similarly as a decrease in the number of collagen cross-linkages.…”

Stress failure and high-altitude pulmonary oedema: mechanistic insights from physiology

“…Although it has been previously shown that rats, rapidly decompressed to extremely low barometric pressures, developed evidence of stress failure [27] the link to HAPE had not been fully established. The strength of the work of BAI et al [26], is the comprehensive and well controlled nature of the study design: animals who were subjected to physiologically relevant levels of hypobaric hypoxia (420 mmHg, altitude ,4,700 m) developed an increase in lung wet-to-dry ratio, and bronchoalveolar lavage fluid total protein, albumin and red blood cell concentrations, indicating that these animals had increased lung water and …”

“…In a carefully controlled study published in this issue, BAI et al [26], working with a rat model, link for the first time direct histological evidence of pulmonary capillary stress failure and the development of a HAPE-like illness. Although it has been previously shown that rats, rapidly decompressed to extremely low barometric pressures, developed evidence of stress failure [27] the link to HAPE had not been fully established.…”