Chronic Hypobaric Hypoxia at High Altitudes Aggravates Chronic Obstructive Pulmonary Disease in Mice.

Objective: Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. However, the effects of chronic hypobaric hypoxia on COPD in high-altitude areas remain controversial. This study aimed to evaluate the impact of chronic hypobaric hypoxia on COPD in high-altitude areas. Methods: C57BL/6J mice were randomized into the sham control (MOCK; intranasal PBS), cigarette smoke extract/lipopolysaccharide (CSE/LPS, CL; intranasal CSE five times/week and LPS twice/week), chronic hypobaric hypoxia (Hy; hypobaric hypoxia at simulated 4000 meters with intranasal PBS), and chronic hypobaric hypoxia plus CL (HyCL; CSE/LPS plus chronic hypobaric hypoxia) groups for 12 weeks. After 12 weeks, pulmonary function, bronchoalveolar lavage fluid cell counts, and pulmonary histopathology were assessed. To elucidate the effects of chronic hypobaric hypoxia on COPD, we performed RNA sequencing on lung tissues to profile molecular alterations and validated key targets using qPCR and Western blotting. Results: The results indicate that chronic hypobaric hypoxia promotes COPD progression, characterized by exacerbated pulmonary function decline, emphysema, as well as small airway remodeling. Transcriptome analysis reveals that "chemical carcinogenesis-reactive oxygen species" and "extracellular matrix-receptor interactions" are common transcriptomic characteristics of COPD both with and without chronic hypobaric hypoxia exposure, whereas inflammatory and immune responses are major transcriptomic signatures driven by chronic hypobaric hypoxia. Furthermore, our results identify Conclusion: These results indicate that chronic hypobaric hypoxia in high-altitude areas promotes COPD progression and correlates with a transcriptomic signature marked predominantly by the activation of inflammatory and immune responses.