Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide

Sean Garrean, Xiao Pei Gao, Victor Brovkovych, Jun Shimizu, You Yang Zhao, Stephen M. Vogel, Asrar B. Malik*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

169 Scopus citations

Abstract

Caveolin-1, the principal structural and signaling protein of caveolae, is implicated in NO-mediated cell signaling events, but its precise role in inflammation is not well understood. Using caveolin-1-knockout (Cav-1 -/-) mice, we addressed the role of caveolin-1 in the lung inflammatory response to sepsis induced by i.p. injection of LPS. LPS-challenged wild-type (WT) lungs exhibited significant increases in neutrophil sequestration (∼16-fold), lung microvascular permeability Kf,c (∼5.7-fold), and edema formation (∼1.6-fold). Compared with WT, Cav-1-/- lungs showed marked attenuation of LPS-induced neutrophil sequestration (∼11-fold increase) and inhibition of microvascular barrier breakdown and edema formation. Prevention of lung injury in Cav-1-/- mice was associated with decreased mortality in response to LPS challenge. To address the basis of the reduced inflammation and injury in Cav-1-/- lungs, we examined the role of NO because its plasma concentration is known to be increased in Cav-1-/- mice. Cav-1-/- mouse lungs demonstrated a significant increase in endothelial NO synthase (eNOS)-derived NO production relative to WT, which is consistent with the role of caveolin-1 as a negative regulator of eNOS activity. Cav-1-/- lungs concurrently showed suppression of NF-κB activity and decreased transcription of inducible NO synthase and ICAM-1. Coadministration of LPS with the NO synthase inhibitor nitro-L-arginine in Cav-1-/- mice prevented the suppression of NF-κB activity and restored lung polymorphonuclear leukocyte sequestration in response to LPS challenge. Thus, caveolin-1, through its ability to regulate eNOS-derived NO production, is a crucial determinant of NF-κB activation and the lung inflammatory response to LPS.

Original languageEnglish (US)
Pages (from-to)4853-4860
Number of pages8
JournalJournal of Immunology
Volume177
Issue number7
DOIs
StatePublished - Oct 1 2006

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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