Cigarette smoke-induced airspace disease in mice develops independently of HIF-1a signaling in leukocytes

The pathogenesis of chronic obstructive pulmonary disease (COPD), a prevalent disease primarily caused by cigarette smoke ex-posure, is incompletely elucidated. Studies in humans and mice have suggested that hypoxia-inducible factor-1a (HIF-1a) may play a role. Reduced lung levels of HIF-1a are associated with decreased vascular density, whereas increased leukocyte HIF-1a may be responsible for increased inflammation. To elucidate the specific role of leukocyte HIF-1a in COPD, we exposed trans -genic mice with conditional deletion or overexpression of HIF-1a in leukocytes to cigarette smoke for 7 mo. Outcomes included pulmonary physiology, aerated lung volumes via microcomputed tomography, lung morphometry and histology, and cardiopul-monary hemodynamics. On aggregate, cigarette smoke increased the aerated lung volume, quasi-static lung compliance, inspira-tory capacity of all strains while reducing the total alveolar septal volume. Independent of smoke exposure, mice with leukocyte -specific HIF-1a overexpression had increased quasi-static compliance, inspiratory capacity, and alveolar septal volume compared with mice with leukocyte-specific HIF-1a deletion. However, the overall development of cigarette smoke-induced lung disease did not vary relative to control mice for either of the conditional strains. This suggests that the development of murine cigarette smoke-induced airspace disease occurs independently of leukocyte HIF-1a signaling.