Caveolin-1 Regulates NF-κB Activation and Lung Inflammatory Response to Sepsis Induced by Lipopolysaccharide

Abstract

Caveolin‐1 (Cav‐1), the principal structural protein of caveolae, is implicated in normal endothelial barrier function, buts its role in lung inflammation is not well understood. Using caveolin‐1 knockout (Cav‐1 −/−) mice, we addressed the role of Cav‐1 in sepsis‐induced lung injury. We assessed lung inflammation in Cav‐1 −/− mice following i.p. injection of LPS. Neutrophil (PMN) binding was measured by an adhesion assay performed on primary cultured mouse endothelial cells. PMN sequestration was assessed by myeloperoxidase activity in the whole lung. Lung microvascular permeability was determined using iodine‐125 radio‐labeled albumin. When compared to wild type (WT) mice, Cav‐1 −/− mice exhibited significantly impaired PMN binding and sequestration after LPS challenge. LPS‐induced increases in lung microvascular permeability and edema formation were also markedly reduced in Cav‐1 −/− mice relative to WT. To address the basis of the reduced lung inflammation, we examined the specific role of nitric oxide (NO). As Cav‐1 is known to sequester eNOS rendering it inactive, we postulated that in Cav‐1 −/− mice there should be increased eNOS activity and eNOS‐derived NO levels in response to LPS challenge. We observed a marked increase in eNOS activity and NO production in Cav‐1 −/− lung relative to WT. Corresponding to the known role of NO in modulating NF‐κB activity, we also noted a time‐dependent suppression of NF‐κB activity in Cav‐1 −/− mice. Thus, Cav‐1 expression and its ability to regulate eNOS‐derived NO production is a crucial determinant of the lung inflammatory response to sepsis. This abstract is funded by: NIH(T32HL007829, HL60678, HL77806)

Elevated Inflammatory Response in Caveolin-1-deficient Mice with Pseudomonas aeruginosa Infection Is Mediated by STAT3 Protein and Nuclear Factor κB (NF-κB)

“…Because caveolins are associated with lipid rafts (54), they are thought to be an important part of the host response to P. aeruginosa infection in lung epithelial cells (7). The majority of previous studies have focused on illustrating the role of caveolins in regulating the cell responses to pathogen virulence factors like LPS (28,(55)(56)(57). However, limited reports have actually investigated the role of Cav-1 in the innate immunity of the lung against P. aeruginosa infection.…”

Deletion of Caveolin-1 Protects against Oxidative Lung Injury via Up-Regulation of Heme Oxygenase-1

“…Recently, cav-1 has also been implicated as a modulator of innate immunity and inflammation (43)(44)(45). The cav-1 2/2 mice displayed increased susceptibility to bacterial infection, whereas macrophages derived from these mice exhibited enhanced inflammatory responses to bacterial endotoxin (43).…”

TLR4 activation of TRPC6-dependent calcium signaling mediates endotoxin-induced lung vascular permeability and inflammation

“…IRAK4 activates its effectors IRAK2 and IRAK1 to induce activation of NF-B and other transcription factors required for the generation of proinflammatory cytokines and reactive oxygen species (ROS) and the activation of MAPK (Medvedev et al, 2002;Kawagoe et al, 2008;Kawai and Akira, 2010;Takeuchi and Akira, 2010). LPS induces lung neutrophil sequestration, as well as neutrophilic and macrophage generation of cytokines and ROS (Andonegui et al, 2002(Andonegui et al, , 2003Gao et al, 2002;Garrean et al, 2006;Bachmaier et al, 2007;Xu et al, 2008;Di et al, 2012), which contribute to the development of ALI (Gao et al, 2002;Bachmaier et al, 2007;Di et al, 2010Di et al, , 2012. However, ECs may also have a more direct role in mediating LPS-induced loss of lung vascular barrier function and inflammation (Andonegui et al, 2002(Andonegui et al, , 2003Wang et al, 2011).…”