Increased lung vascular permeability is an important contributor to respiratory failure in acute lung injury (ALI). We found that a function-blocking antibody against the integrin ␣v␤5 prevented development of lung vascular permeability in two different models of ALI: ischemia-reperfusion in rats (mediated by vascular endothelial growth factor [VEGF]) and ventilation-induced lung injury (VILI) in mice (mediated, at least in part, by transforming growth factor-␤ [TGF-␤]). Knockout mice homozygous for a null mutation of the integrin ␤5 subunit were also protected from lung vascular permeability in VILI. In pulmonary endothelial cells, both the genetic absence and blocking of ␣v␤5 prevented increases in monolayer permeability induced by VEGF, TGF-␤, and thrombin. Furthermore, actin stress fiber formation induced by each of these agonists was attenuated by blocking ␣v␤5, suggesting that ␣v␤5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin ␣v␤5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.Keywords: integrin ␣v␤5; lung vascular permeability; pulmonary endothelial barrier function Acute lung injury (ALI) is a devastating clinical syndrome characterized by development of pulmonary edema and flooding of alveolar spaces leading to impaired gas exchange, arterial hypoxemia, and respiratory failure (1). While much progress has been made in understanding the pathogenesis of ALI, it is estimated that 190,600 cases of ALI occur every year in the United States alone; these are associated with 74,500 deaths and 3.6 million hospital days (2). Effective pharmacologic therapies are not currently available and the molecular mechanisms regulating ALI remain poorly understood.Vascular permeability in the lung has long been considered a principal pathologic hallmark of ALI that is largely responsible for its characteristic pulmonary edema formation (3, 4). Recently, integrin ␣v␤5, a member of the integrin family of heterodimeric transmembrane cell surface receptors, was shown to specifically regulate increases in vascular permeability induced by vascular endothelial growth factor (VEGF) in the systemic circulation (5). Although regulation of permeability in the systemic and pulmonary circulations is often physiologically dis- CLINICAL RELEVANCEWe describe a novel role for integrin ␣v␤5 in regulating lung vascular permeability and agonist-induced endothelial permeability. Furthermore, we suggest that ␣v␤5 regulation of the actin-cytoskeleton may be a mechanism responsible for these effects.tinct, and the precise role of VEGF in ALI remains controversial, we hypothesized that ␣v␤5 could be an important regulator of vascular permeability in the lung. Therefore, we sought to determine whether ␣v␤5 could regulate lung vascular permeability in in vivo models of ALI.In this report, we used two in vivo models of ALI to examine the role of ␣v␤5 in regulating lung vascular p...

Lung endothelial damage is a characteristic morphological feature of ischemia-reperfusion (I/R) injury, although the molecular steps involved in the loss of endothelial integrity are still poorly understood. We tested the hypothesis that the activation of vascular endothelial growth factor (VEGF) cell signaling would be responsible for the increase in lung vascular permeability seen early after the onset of I/R in rats. Furthermore, we hypothesized that the I/R-induced pulmonary edema would be significantly attenuated in rats by the activation of the stress protein response. Pretreatment with Ad Flk-1, an adenovirus encoding for the soluble VEGF receptor type II, prevented I/R-mediated increase in lung vascular permeability in rats. Furthermore, the I/R-induced lung injury was significantly decreased by prior activation of the stress protein response with geldanamycin or pyrrolidine dithiocarbamate. In vitro studies demonstrated that VEGF caused an increase in protein permeability across primary cultures of bovine macro- and microvascular lung endothelial cell monolayers that were associated with a phosphorylation of VE- and E-cadherin and the formation of actin stress fibers. Activation of the stress protein response prevented the VEGF-mediated changes in protein permeability across these cell monolayers and reduced the phosphorylation of VE-and E-cadherins, as well as the formation of actin stress fibers in these cells.

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