Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1.
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 p38beta 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.
Jin
Yang
Y
Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
Kim
Hong Pyo
HP
Chi
Minli
M
Ifedigbo
Emeka
E
Ryter
Stefan W
SW
Choi
Augustine M K
AM
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D051242:Caveolin 1 / Q000235:genetics / Q000502:physiology*; D016923:Cell Death; D042783:Endothelial Cells / Q000473:pathology; D004847:Epithelial Cells / Q000473:pathology; D005347:Fibroblasts / Q000473:pathology; D051547:Heme Oxygenase-1 / Q000096:biosynthesis*; D018496:Hyperoxia / Q000150:complications; D007093:Imidazoles / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress; D010766:Phosphorylation; D011524:Protoporphyrins / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D012128:Respiratory Distress Syndrome / Q000201:enzymology* / Q000209:etiology / Q000401:mortality; D015854:Up-Regulation; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism
D051242:Caveolin 1; D007093:Imidazoles; D011524:Protoporphyrins; D011725:Pyridines; C028025:protoporphyrin IX; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C090942:4-(4-fluorophenyl)-2-(4-hydroxyphenyl)-5-(4-pyridyl)imidazole