This Article Full Text Full Text (PDF) All Versions of this Article: 2007-0323OCv1 39/2/171    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 Google Scholar Articles by Jin, Y. Articles by Choi, A. M. K. PubMed PubMed Citation Articles by Jin, Y. Articles by Choi, A. M. K.

Deletion of Caveolin-1 Protects against Oxidative Lung Injury via Up-Regulation of Heme Oxygenase-1

¹ Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; and ² Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts

Correspondence and requests for reprints should be addressed to Augustine M. K. Choi, M.D., Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115. E-mail: amchoi{at}rics.bwh.harvard.edu

Acute lung injury (ALI) is a major cause of morbidity and mortality in critically ill patients. Hyperoxia causes lung injury in animals and humans, and is an established model of ALI. Caveolin-1, a major constituent of caveolae, regulates numerous biological processes, including cell death and proliferation. Here we demonstrate that caveolin-1–null mice (cav-1^–/–) were resistant to hyperoxia-induced death and lung injury. Cav-1^–/– mice sustained reduced lung injury after hyperoxia as determined by protein levels in bronchoalveolar lavage fluid and histologic analysis. Furthermore, cav-1^–/– fibroblasts and endothelial cells and cav-1 knockdown epithelial cells resisted hyperoxia-induced cell death in vitro. Basal and inducible expression of the stress protein heme oxygenase-1 (HO-1) were markedly elevated in lung tissue or fibroblasts from cav-1^–/– mice. Hyperoxia induced the physical interaction between cav-1 and HO-1 in fibroblasts assessed by co-immunoprecipitation studies, which resulted in attenuation of HO activity. Inhibition of HO activity with tin protoporphyrin-IX abolished the survival benefits of cav-1^–/– cells and cav-1^–/– mice exposed to hyperoxia. The cav-1^–/– mice displayed elevated phospho-p38 mitogen-activated protein kinase (MAPK) and p38β expression in lung tissue/cells under basal conditions and during hyperoxia. Treatment with SB202190, an inhibitor of p38 MAPK, decreased hyperoxia-inducible HO-1 expression in wild-type and cav-1^–/– fibroblasts. Taken together, our data demonstrated that cav-1 deletion protects against hyperoxia-induced lung injury, involving in part the modulation of the HO-1–cav-1 interaction, and the enhanced induction of HO-1 through a p38 MAPK–mediated pathway. These studies identify caveolin-1 as a novel component involved in hyperoxia-induced lung injury.

Key Words: acute lung injury • acute respiratory distress syndrome • caveolin-1 • heme oxygenase-1

CLINICAL RELEVANCE This novel study demonstrates that deletion of caveolin-1 confers protection against hyperoxia-induced lung injury and promotes survival in mice via heme oxygenase-1. This may provide additional therapeutic targets in the management or prevention of acute lung injury/acute respiratory distress syndrome.