This Article Full Text Full Text (PDF) All Versions of this Article: 2008-0003OCv1 40/3/332    most recent Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Zhang, S. X. L. Articles by Wang, Y. Search for Related Content PubMed PubMed Citation Articles by Zhang, S. X. L. Articles by Wang, Y.

Type I Epithelial Cells Are the Main Target of Whole-Body Hypoxic Preconditioning in the Lung

¹ Kosair Children's Hospital Research Institute, Department of Pediatrics, ² Department of Pathology and Laboratory Medicine, and ⁴ Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky; and ³ Department of Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, Pennsylvania

Correspondence and requests for reprints should be addressed to Yang Wang, M.D., Ph.D., Department of Pediatrics, University of Louisville, 570 S. Preston Street, Ste. 211, Louisville, KY 40202. 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 hours with or without pretreatment of WHPC ([8% O₂] x 10 min/[21% O₂] 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.

Key Words: pulmonary edema • high-altitude diseases • alveolar fluid clearance • cytoprotection • pulmonary hypertension

CLINICAL RELEVANCE Type I cells are both the target injury site for hypoxia in the lung and the targeted cell type for protection by whole-body hypoxic preconditioning. This suggests they should be considered as the primary target for therapy, given their newly-defined role in alveolar fluid clearance.

 

This article has been cited by other articles:

				U. Pfeil, M. Aslam, R. Paddenberg, K. Quanz, C. L. Chang, J.-I. Park, B. Gries, A. Rafiq, P. Faulhammer, A. Goldenberg, et al. Intermedin/adrenomedullin-2 is a hypoxia-induced endothelial peptide that stabilizes pulmonary microvascular permeability Am J Physiol Lung Cell Mol Physiol, November 1, 2009; 297(5): L837 - L845. [Abstract] [Full Text] [PDF]