title: Alveolar-capillary adaptation to chronic hypoxia in the fatty lung.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX, USA.
authors.forename: C
authors.initials: C
authors.lastname: Yilmaz
authors.forename: P
authors.initials: P
authors.lastname: Ravikumar
authors.forename: D
authors.initials: D
authors.lastname: Gyawali
authors.forename: R
authors.initials: R
authors.lastname: Iyer
authors.forename: R H
authors.initials: RH
authors.lastname: Unger
authors.forename: C C W
authors.initials: CC
authors.lastname: Hsia
mesh_terms: D000222:Adaptation, Physiological; D000818:Animals; D004249:DNA Damage; D005260:Female; D000860:Hypoxia / Q000150:complications*; D008297:Male; D009765:Obesity / Q000150:complications / Q000473:pathology; D009929:Organ Size; D011247:Pregnancy; D011650:Pulmonary Alveoli / Q000098:blood supply* / Q000502:physiology*; D051381:Rats
keywords: High-altitude adaptation; lipotoxicity; lung function; lung morphometry; metabolic syndrome; obesity