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J. Biol. Chem., Vol. 282, Issue 33, 24109-24119, August 17, 2007

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Acute Lung Injury Edema Fluid Decreases Net Fluid Transport across Human Alveolar Epithelial Type II Cells^*

Jae W. Lee¹, Xiaohui Fang, Gregory Dolganov^¶, Richard D. Fremont^||, Julie A. Bastarache^||, Lorraine B. Ware^||, and Michael A. Matthay

From the Departments of Anesthesiology and Medicine and the Cardiovascular Research Institute, University of California, San Francisco, California 94143, ^¶Department of Medicine, Stanford University Medical Center, Stanford, California 94305, and ^||Division of Allergy, Pulmonary, and Critical Care Medicine, Department of Medicine, Vanderbilt University School of Medicine, Nashville, Tennessee 37232

Most patients with acute lung injury (ALI) have reduced alveolar fluid clearance that has been associated with higher mortality. Several mechanisms may contribute to the decrease in alveolar fluid clearance. In this study, we tested the hypothesis that pulmonary edema fluid from patients with ALI might reduce the expression of ion transport genes responsible for vectorial fluid transport in primary cultures of human alveolar epithelial type II cells. Following exposure to ALI pulmonary edema fluid, the gene copy number for the major sodium and chloride transport genes decreased. By Western blot analyses, protein levels of ENaC, 1Na,K-ATPase, and cystic fibrosis transmembrane conductance regulator decreased as well. In contrast, the gene copy number for several inflammatory cytokines increased markedly. Functional studies demonstrated that net vectorial fluid transport was reduced for human alveolar type II cells exposed to ALI pulmonary edema fluid compared with plasma (0.02 ± 0.05 versus 1.31 ± 0.56 µl/cm²/h, p < 0.02). An inhibitor of p38 MAPK phosphorylation (SB202190) partially reversed the effects of the edema fluid on net fluid transport as well as gene and protein expression of the main ion transporters. In summary, alveolar edema fluid from patients with ALI induced a significant reduction in sodium and chloride transport genes and proteins in human alveolar epithelial type II cells, effects that were associated with a decrease in net vectorial fluid transport across human alveolar type II cell monolayers.

Received for publication, January 29, 2007 , and in revised form, May 29, 2007.

^* This work was supported by NHLBI, National Institutes of Health Grants HL-51856 and HL-51854 (to M. A. M.) and HL081332 (to L. B. W.) and by the John Severinghaus Fellowship (to J. W. L.). The abstract was presented in part at the American Thoracic Society Meeting, May 19–24, 2006 in San Diego, CA. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Anesthesiology, University of California, 505 Parnassus Ave., Box 0648, San Francisco, CA 94143. Tel.: 415-476-1079; Fax: 415-502-2126; E-mail: leejw{at}anesthesia.ucsf.edu.

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