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)

No abstract