Type I epithelial cells are the main target of whole-body hypoxic preconditioning in the lung.
Whole-body hypoxic preconditioning (WHPC) prolongs survival of mice exposed to severe hypoxia by attenuating pulmonary edema and preserving gas exchange. However, the cellular and molecular mechanism(s) of this protection remains unclear. The objective of this study was to identify the cellular target(s) of WHPC in the lung. Conscious mice were exposed to hypoxia (7% O(2)) for 6 hours with or without pretreatment of WHPC ([8% O(2)] x 10 min/[21% O(2)] x 10 min; 6 cycles). Hypoxia caused severe lung injury, as shown by the development of high-permeability-type pulmonary edema and the release of lactate dehydrogenase and creatine kinase into the airspace and the circulation. All these signs of hypoxic lung injury were significantly attenuated by WHPC. Hypoxia also caused a remarkable release of type I cell markers (caveolin-2 and receptor for advanced glycation end products) in lung lavage that was almost completely abolished by WHPC. Conversely, hypoxia-induced release of type II cell markers (surfactant-associated proteins A and D) was only marginal, and was unaffected by WHPC. Electron microscopic analysis demonstrated considerable hypoxic damage in alveolar type I cells and vascular endothelial cells. Notably, WHPC completely eliminated hypoxic damage in the former and alleviated it in the latter. Type II cells appeared normal. Furthermore, WHPC up-regulated protein expression of cytoprotective genes in the lung, such as heat shock proteins and manganese superoxide dismutase. Thus, WHPC attenuates hypoxic lung injury through protection of cells constituting the respiratory membrane, especially hypoxia-vulnerable type I epithelial cells. This beneficial effect may involve up-regulation of cytoprotective genes.
Zhang
Shelley X L
SX
Department of Pediatrics, University of Louisville, 570 S. Preston Street, Ste. 211, Louisville, KY 40202, USA.
Miller
James J
JJ
Stolz
Donna Beer
DB
Serpero
Laura D
LD
Zhao
Wei
W
Gozal
David
D
Wang
Yang
Y
D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D019610:Cytoprotection / Q000235:genetics; D004847:Epithelial Cells / Q000502:physiology* / Q000648:ultrastructure; D000860:Hypoxia / Q000378:metabolism* / Q000473:pathology; D008168:Lung / Q000166:cytology* / Q000473:pathology / Q000502:physiology*; D055370:Lung Injury / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D014841:von Willebrand Factor / Q000276:immunology / Q000378:metabolism
D015415:Biomarkers; C029417:Von Willebrand antigen; D014841:von Willebrand Factor
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