title: Caveolin-1 regulates NF-kappaB activation and lung inflammatory response to sepsis induced by lipopolysaccharide.
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 (approximately 16-fold), lung microvascular permeability K(f,c) (approximately 5.7-fold), and edema formation (approximately 1.6-fold). Compared with WT, Cav-1(-/-) lungs showed marked attenuation of LPS-induced neutrophil sequestration (approximately 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-kappaB 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-kappaB 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-kappaB activation and the lung inflammatory response to LPS.
authors.affiliation: Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, 835 South Wolcott Avenue, Chicago, IL 60612, USA.
authors.forename: Sean
authors.initials: S
authors.lastname: Garrean
authors.forename: Xiao-Pei
authors.initials: XP
authors.lastname: Gao
authors.forename: Victor
authors.initials: V
authors.lastname: Brovkovych
authors.forename: Jun
authors.initials: J
authors.lastname: Shimizu
authors.forename: You-Yang
authors.initials: YY
authors.lastname: Zhao
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Vogel
authors.forename: Asrar B
authors.initials: AB
authors.lastname: Malik
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002199:Capillary Permeability; D051242:Caveolin 1 / Q000235:genetics / Q000378:metabolism*; D024202:Electrophoretic Mobility Shift Assay; D042783:Endothelial Cells / Q000276:immunology / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000378:metabolism*; D009504:Neutrophils / Q000276:immunology; D009569:Nitric Oxide / Q000378:metabolism*; D052247:Nitric Oxide Synthase Type II / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology / Q000276:immunology*; D011654:Pulmonary Edema / Q000209:etiology / Q000276:immunology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000139:chemically induced / Q000150:complications*
chemical_list: D051242:Caveolin 1; D004791:Enzyme Inhibitors; D008070:Lipopolysaccharides; D016328:NF-kappa B; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II; D052250:Nitric Oxide Synthase Type III