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

Am J Physiol Lung Cell Mol Physiol. 2022 Oct 1;323(4):L391-L399. doi: 10.1152/ajplung.00491.2021. Epub 2022 Aug 9.


The pathogenesis of chronic obstructive pulmonary disease (COPD), a prevalent disease primarily caused by cigarette smoke exposure, is incompletely elucidated. Studies in humans and mice have suggested that hypoxia-inducible factor-1α (HIF-1α) may play a role. Reduced lung levels of HIF-1α are associated with decreased vascular density, whereas increased leukocyte HIF-1α may be responsible for increased inflammation. To elucidate the specific role of leukocyte HIF-1α in COPD, we exposed transgenic mice with conditional deletion or overexpression of HIF-1α in leukocytes to cigarette smoke for 7 mo. Outcomes included pulmonary physiology, aerated lung volumes via microcomputed tomography, lung morphometry and histology, and cardiopulmonary hemodynamics. On aggregate, cigarette smoke increased the aerated lung volume, quasi-static lung compliance, inspiratory capacity of all strains while reducing the total alveolar septal volume. Independent of smoke exposure, mice with leukocyte-specific HIF-1α overexpression had increased quasi-static compliance, inspiratory capacity, and alveolar septal volume compared with mice with leukocyte-specific HIF-1α 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-1α signaling.

Keywords: HIF-1α; cigarette smoke; emphysema; macrophage.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Cigarette Smoking*
  • Disease Models, Animal
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Leukocytes
  • Lung / pathology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Nicotiana / adverse effects
  • Pulmonary Disease, Chronic Obstructive* / etiology
  • Pulmonary Disease, Chronic Obstructive* / pathology
  • Pulmonary Emphysema* / pathology
  • X-Ray Microtomography


  • Hypoxia-Inducible Factor 1, alpha Subunit

Associated data

  • figshare/10.6084/m9.figshare.17114123.v4