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B Activation and Lung Inflammatory Response to Sepsis Induced by Lipopolysaccharide1
Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois College of Medicine, Chicago, IL 60612
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-
B 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-B 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-B activation and the lung inflammatory response to LPS.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This study was supported by National Institutes of Health Grants T32 HL07829 (to S.G.), HL60678, HL46350, and HL077806, and the Eleanor B. Pillsbury Fellowship–University of Illinois Hospital (to S.G.).
2 S.G. and X.-P.G. contributed equally to this work.
3 Address correspondence and reprint requests to Dr. Asrar B. Malik, Department of Pharmacology, University of Illinois College of Medicine, 835 South Wolcott Avenue (M/C 868), Chicago, IL 60612. E-mail address: abmalik{at}uic.edu
4 Abbreviations used in this paper: eNOS, endothelial NO synthase; iNOS, inducible NO synthase; PMN, polymorphonuclear leukocyte; L-NA, nitro-L-arginine; WT, wild type; MLVEC, mouse lung vascular endothelial cell; MPO, myeloperoxidase; siRNA, small interfering RNA.
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