Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1

Yang Jin, Pyo Kim Hong, Minli Chi, Emeka Ifedigbo, Stefan W. Ryter, Augustine M.K. Choi

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)171-179
Number of pages9
JournalAmerican Journal of Respiratory Cell and Molecular Biology
Volume39
Issue number2
DOIs
StatePublished - Aug 1 2008

Keywords

  • Acute lung injury
  • Acute respiratory distress syndrome
  • Caveolin-1
  • Heme oxygenase-1

ASJC Scopus subject areas

  • Molecular Biology
  • Pulmonary and Respiratory Medicine
  • Clinical Biochemistry
  • Cell Biology

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