Improved Pulmonary Gas Exchange at Altitude Is Due to Pulmonary Vascular Adaptation to Chronic Hypoxia in Urban Residents

Willixhofer, Robin, Laura Gochicoa-Rangel, Anna Apostolo, Jeness Campodonico, Elisabetta Salvioni, Ada De-Los- Santos-Martínez, Alejandro Reyes-García, Luis Torre-Bouscoulet, Sergio Harari, Federico Tagariello, and Piergiuseppe Agostoni. Improved pulmonary gas exchange at altitudes is due to pulmonary vascular adaptation to chronic hypoxia in urban residents. High Alt Med Biol. 00:00-00, 2025. Background: Chronic exposure to high altitude induces physiological adaptations in the lung, but the specific mechanisms of alveolar-capillary gas exchange adaptation in urban populations remain incompletely understood. Methods: We assessed altitude-related alveolar capillary membrane gas diffusion adaptations in Milan (lowlanders, 120 m) and Mexico City (highlanders, 2,240 m). A 1:1 nearest-neighbor matching by age and sex was performed. Results: Comparison between healthy young adults (n = 246, age <40 years) showed higher diffusing capacity for carbon monoxide (DLCO: 31.7 [27.4-39.0] vs. 28.2 [24.6-32.8] ml/min/mmHg, p < 0.0001) and pulmonary capillary blood volume (Vcap: 105 [87-113] vs. 84 [71-98] ml, p < 0.0001), but lower membrane diffusing capacity (Dm: 50 [45-60] vs. 61 [51.70] ml/min/mmHg, p < 0.0001) in highlanders. The matching procedure yielded 71 pairs (n = 142) with balanced age and sex distributions (standardized mean differences <0.1). These differences remained significant after matching: highlanders showed higher DLCO (31.7 [27.8-39.1] vs. 27.1 [23.7-32.4] ml/min/mmHg, p < 0.0001), higher Vcap (104 [85-124] vs. 78 [65-96] ml, p < 0.0001), and lower Dm (51 [46-60 vs. 57 [50-68] ml/min/mmHg, p = 0.045). Conclusions: These findings suggest vascular, rather than membrane, adaptation to chronic hypoxia in high-altitude urban residents.