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 ␣v5 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 ␣v5 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 ␣v5, suggesting that ␣v5 regulates induced pulmonary endothelial permeability by facilitating interactions with the actin cytoskeleton. These results identify integrin ␣v5 as a central regulator of increased pulmonary vascular permeability and a potentially attractive therapeutic target in ALI.Keywords: integrin ␣v5; 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 ␣v5, 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 ␣v5 in regulating lung vascular permeability and agonist-induced endothelial permeability. Furthermore, we suggest that ␣v5 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 ␣v5 could be an important regulator of vascular permeability in the lung. Therefore, we sought to determine whether ␣v5 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 ␣v5 in regulating lung vascular p...
Cyanidin-3-O-glucoside (C3G), an anthocyanin belonging to the flavonoid family and commonly present in food and vegetables in human diet, has exhibited anti-inflammatory and anti-oxidant effects. This study aimed to investigate the protective ability of C3G against inflammatory and oxidative injuries, as well as to clarify the possible mechanism in lipopolysaccharide (LPS)-stimulated human umbilical vein endothelial cells (HUVECs) in vitro and acute respiratory distress syndrome mouse model in vivo. HUVECs or male Kunming mice were pretreated with C3G 1 h before LPS stimulation. C3G significantly inhibited the production of pro-inflammatory cytokines (tumor necrosis factor-α, interleukin (IL) -6, and IL-1β) in cell supernatants and bronchoalveolar lavage fluid (BALF) as determined by enzyme-linked immunosorbent assay. Histopathologic examination with hematoxylin and eosinstaining showed that C3G pretreatment substantially suppressed inflammatory cell infiltration, alveolar wall thickening, and interstitial edemain lung tissues. C3G markedly prevented LPS-induced elevation of malondialdehyde and myeloperoxidase levels in lung tissue homogenates, wet to dry ratio of lung tissues, total cells, and inflammatory cells (neutrophils and macrophages) in BALF. Moreover, C3G reduced superoxide dismutase activity in the lung tissue homogenates. Western blot assay also showed that C3G pretreatment significantly suppressed LPS-induced activation of nuclear factor-kappaB (NF-κB) and mitogen-activated protein kinase (MAPK) signaling pathways by blocking the phosphorylation of inhibitor κB-α, NF-κB/P65, extracellular signal-regulated kinase, p38, and c-Jun NH2-terminal kinase in the lung tissues. In summary, C3G may ameliorate LPS-induced injury, which results from inflammation and oxidation, by inhibiting NF-κB and MAPK pathways and playing important anti-inflammatory and anti-oxidative roles.
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