Integrin αvβ5 Regulates Lung Vascular Permeability and Pulmonary Endothelial Barrier Function

Abstract

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...

Anchoring Fusion Thrombomodulin to the Endothelial Lumen Protects against Injury-induced Lung Thrombosis and Inflammation

“…In a lung model of I/R, characterized by downregulation of TM along with activation of coagulation and inflammation (30)(31)(32)(33)35), scFv/TM was superior to sTM in reducing fibrin deposition and cytokine production and provided greater protection of lung function. scFv/TM also inhibited elevation of Egr-1, a pivotal participant in I/R-mediated lung injury (31,33,45).…”

“…I/R causes thrombosis and inflammation (32)(33)(34)(35)(36)(37)(38). We detected reduced expression of TM and a concomitant increase in the deposition of fibrin in lungs after I/R ( Figure 3A).…”

Stromal regulation of vessel stability by MMP14 and TGFβ

“…For example, in bleomycin-induced pulmonary edema, TGFb promotes vascular leakage by acting directly on pulmonary endothelial cells in concert with integrin a5b1 (Pittet et al, 2001;Su et al, 2007). TGFb also induces the expression of angiopoietin-like protein 4 (Angpt-4) that, in turn, disrupts endothelial cell junctions, increases leakage, and promotes tumor cell emigration and metastasis to the lungs (Padua et al, 2008).…”

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“…Sheppard et al [74,75] have demonstrated that β3 is protective (i.e.,β5-null mice are sensitive) to endotracheal and intraperitoneal LPS and cecal ligation and puncture (CLP), whereas Pittet et al have shown that β5 enhances (i.e.,β5-null mice are resistant) to lung vascular leak after infection, [76] ischemia/reperfusion, or VILI [77]. Meanwhile, a new publication by Ding [78] suggested that the integrin family member β-6 is known to play an important role in regulating lung inflammation, macrophage protease expression, and pulmonary edema during the process of ALI.…”