TY - JOUR
T1 - Caveolin-1 regulates NF-κB activation and lung inflammatory response to sepsis induced by lipopolysaccharide
AU - Garrean, Sean
AU - Gao, Xiao Pei
AU - Brovkovych, Victor
AU - Shimizu, Jun
AU - Zhao, You Yang
AU - Vogel, Stephen M.
AU - Malik, Asrar B.
PY - 2006/10/1
Y1 - 2006/10/1
N2 - 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.
AB - 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.
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U2 - 10.4049/jimmunol.177.7.4853
DO - 10.4049/jimmunol.177.7.4853
M3 - Article
C2 - 16982927
AN - SCOPUS:33749154295
VL - 177
SP - 4853
EP - 4860
JO - Journal of Immunology
JF - Journal of Immunology
SN - 0022-1767
IS - 7
ER -