Published ahead of print on September 5, 2008, doi:10.1165/rcmb.2008-0003OC Am. J. Respir. Cell Mol. Biol., Volume 40, Number 3, March 2009, 332-339 A more recent version of this article appeared on March 1, 2009
Submitted on January 2, 2008 Type I Epithelial Cells Are the Main Target of Whole-body Hypoxic Preconditioning in the LungShelley X.L. Zhang1,1 Department of Pediatrics, University of Louisville, Kosair Children's Hospital Research Institute, Louisville, KY, USA, 2 Department of Pathology and Laboratory Medicine, University of Louisville, Louisville, KY, USA, 3 Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, PA, USA, 4 Department of Pediatrics, University of Louisville, Kosair Children's Hospital Research Institute, Louisville, KY, USA; Department of Pharmacology and Toxicology, University of Louisville, Louisville, KY, USA * To whom correspondence should be addressed. E-mail: y.wang{at}louisville.edu.
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% O2) for 6 h with or without pretreatment of WHPC ([8% O2]x10-min/[21% O2]x10-min, 6 cycles). Hypoxia caused severe lung injury as evidenced 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 that in the latter. Type II cells appeared normal. Furthermore, WHPC upregulated 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 upregulation of cytoprotective genes.
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