Abstract 85: Caveolin-1 Regulates Acute Lung Vascular Injury by Modulating Endothelial Permeability and Neutrophil Activation
During inflammation, polymophorneuclear neutrophil (PMN) activation alters the structural and functional integrity of the vascular endothelial barrier. The objective of the study was to address the role of caveolin-1 in PMN-induced acute lung injury. Mice were challenged with formyl-Met-Leu-Phe (fMLP, 20 μg/kg, iv.) for 4 h. In wild-type (wt) mice, fMLP caused pulmonary edema. However, caveolin-1 null mice (Cav1-/-) were protected from lung microvascular injury and edema formation. In the isolated-perfused wt mouse lungs, infusion of PMNs (2 × 106) followed by fMLP (1.0 μM) infusion for 30 min also increased transvascular 125I-albumin permeability but the response was prevented in Cav1-/- lungs. In pulmonary microvascular endothelial cells, PMN activation induced phosphorylation of caveolin-1 and increased transendothelial 125I-albumin transport. Downregulation of caveolin-1 expression with siRNA abolished the PMN-induced increase in transendothelial albumin permeability. Freshly-isolated PMNs from Cav1-/- mice showed a 2- to 4-fold reduction in phorbol ester- or fMLP-stimulated superoxide production compared to wt PMNs. Thus, caveolin-1 contributes to PMN-mediated acute lung injury by modulating PMN superoxide production and increasing transendothelial albumin permeability. These data suggest that caveolin-1 is a therapeutic target in treating inflammatory lung microvascular injury.