Role of Caveolin‐1 Expression in the Pathogenesis of Pulmonary Edema in Ventilator‐Induced Lung Injury

Caveolin‐1 is a key regulator of pulmonary endothelial barrier function. Here, we tested the hypothesis that caveolin‐1 expression is required for ventilator‐induced lung injury (VILI). Caveolin‐1 gene‐disrupted (Cav‐1 −/− ) and age‐, sex‐, and strain‐matched wild‐type (WT) control mice were ventilated using two protocols: volume‐controlled with protective (8 mL/kg) versus injurious (21 mL/Kg) tidal volume for up to 6 hours; and pressure‐controlled with protective (airway pressure = 12 cm H 2 O) versus injurious (30 cm H 2 O) ventilation to induce lung injury. Lung microvascular permeability (whole‐lung 125 I‐albumin accumulation, lung capillary filtration coefficient [K f, c ]) and inflammatory markers (bronchoalveolar lavage [BAL] cytokine levels and neutrophil counts) were measured. We also evaluated histologic sections from lungs, and the time course of Src kinase activation and caveolin‐1 phosphorylation. VILI induced a 1.7‐fold increase in lung 125 I‐albumin accumulation, fourfold increase in K f, c ’ significantly increased levels of cytokines CXCL1 and interleukin‐6, and promoted BAL neutrophilia in WT mice. Lung injury by these criteria was significantly reduced in Cav‐1 −/− mice but fully restored by i.v. injection of liposome/Cav‐1 cDNA complexes that rescued expression of Cav‐1 in lung microvessels. As thrombin is known to play a significant role in mediating stretch‐induced vascular injury, we observed in cultured mouse lung microvascular endothelial cells (MLECs) thrombin‐induced albumin hyperpermeability and phosphorylation of p44/42 MAP kinase in WT but not in Cav‐1 −/− MLECs. Thus, caveolin‐1 expression is required for mechanical stretch‐induced lung inflammation and endothelial hyperpermeability in vitro and in vivo.