Abstract
High-altitude pulmonary edema (HAPE) is non-cardiogenic pulmonary edema that occurs in healthy individuals who are unable to acclimatize when they ascend above 2,500-3,000 m above sea level in a few days. The pathogenesis of HAPE is complex and it is difficult to explain it by a single mechanism. Currently recognized pathogenesis is related to altered pulmonary hemodynamics, increased pulmonary capillary permeability, inflammatory response, dysregulated sodium-water transport, and impaired alveolar fluid clearance, and it is caused by a combination of causes. A high-altitude environment is both hypobaric and hypoxic, and whether hypobaria contributes to the pathogenesis of HAPE is unknown. We established a model in which 30 Institute of Cancer Research Mice (ICR mice) were divided into normal control (C, n = 6), normobaric hypoxic (CH, n = 8), hypobaric normoxic (HC, n = 8), and hypobaric hypoxic (HH, n = 8) groups. The simulated altitude was 5,000 m above sea level. Lung tissue wet/dry (W/D) ratios were determined, and molecular and histologic examinations were performed on each animal. W/D ratios were increased in the CH, HC, and HH groups compared to controls. ELISA revealed increased IL-1β expression in the HC and HH groups and markedly elevated TNF-α levels in the HH group. Histologic sections disclosed septal thickening and edema with inflammatory cell infiltration in the CH, HC, and HH groups compared with the control group. The HH group exhibited the most severe histopathologic abnormalities that included septal rupture. Electron microscopy demonstrated injury to endothelial and epithelial membranes and disruption of the integrity of the air-blood barrier after hypobaric and/or hypoxic exposures. Our study establishes a direct link between the histologic and physiologic findings of HAPE-like disease and demonstrates that normoxic hypobaria incites HAPE-like pathology. Furthermore, hypoxia and hypobaria act synergistically and stimulate inflammation in ICR mice. Therefore, we suggest that hypobaria plays an important role in the pathogenesis of HAPE.