Deletion of caveolin-1 protects against oxidative lung injury via up-regulation of heme oxygenase-1 Academic Article uri icon

Overview

MeSH Major

  • Caveolin 1
  • Heme Oxygenase-1
  • Oxidative Stress
  • Respiratory Distress Syndrome, Adult

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 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.

publication date

  • August 2008

Research

keywords

  • Academic Article

Identity

Language

  • eng

PubMed Central ID

  • PMC2542454

Digital Object Identifier (DOI)

  • 10.1165/rcmb.2007-0323OC

PubMed ID

  • 18323531

Additional Document Info

start page

  • 171

end page

  • 9

volume

  • 39

number

  • 2