Abstract
AIM: Obese diabetic (ZDF fa/fa) rats with genetic leptin resistance suffer chronic lipotoxicity associated with age-related lung restriction and abnormal alveolar ultrastructure. We hypothesized that these abnormalities impair adaptation to ambient hypoxia. METHODS: Male fa/fa and lean (+/+) ZDF rats (4-months old) were exposed to 21 or 13% O2 for 3 weeks. Lung function was measured under anaesthesia. Lung tissue was assayed for DNA damage and ultrastructure measured by morphometry. RESULTS: In normoxia, lung volume, compliance and diffusing capacity were lower, while blood flow was higher in fa/fa than +/+ rats. In hypoxia, fa/fa animals lost more weight, circulating hematocrit rose higher, and lung volume failed to increase compared to +/+. In fa/fa, the hypoxia-induced increase in post-mortem lung volume was attenuated (19%) vs. +/+ (39%). Alveolar ducts were 35% smaller in normoxia but enlarged twofold more in hypoxia compared to +/+. Hypoxia induced broad increases (90-100%) in the volumes and surface areas of alveolar septal components in +/+ lungs; these increases were moderately attenuated in fa/fa lungs (58-75%), especially that of type II epithelium volume (16 vs. 61% in +/+). In fa/fa compared to +/+ lungs, oxidative DNA damage was greater with increased hypoxia induced efflux of alveolar macrophages. Harmonic mean thickness of the diffusion barrier was higher, indicating higher structural resistance to gas transfer. CONCLUSION: Chronic lipotoxicity impaired hypoxia-induced lung expansion and compensatory alveolar growth with disproportionate effect on resident alveolar progenitor cells. The moderate structural impairment was offset by physiological adaptation primarily via a higher hematocrit.