Integrin Beta 4 in Vascular Inflammatory Responses

描述(由申请人提供)：急性炎症性肺损伤(ALI)是重症监护病房中常见的具有挑战性的临床问题，与显著的发病率和死亡率相关。ALI的一个基本特征是肺血管通透性增加，这通常是由活跃的炎症反应和随后的内皮屏障破坏引起的。旨在减轻血管通透性的策略可以提供有吸引力的新的治疗靶点和方法。我们先前在小鼠ALI模型中发现了HMG辅酶A还原酶抑制剂辛伐他汀的保护作用，并确定了他汀类药物的有效抗炎作用，包括增强内皮细胞(EC)屏障功能。对辛伐他汀介导的EC基因表达的基因组研究证实，整合素4显著上调，整合素4是一种在包括EC在内的多种细胞类型中表达的层粘连蛋白受体，提示可能是ALI的新靶点。虽然关于整合素？4在EC中的作用的信息有限，但整合素被认为是炎症信号的媒介，我们最近在不同的小鼠ALI和呼吸机诱导的肺损伤(VILI)模型中证实了与抑制整合素？4相关的肺部炎症减轻。因此，我们现在假设，整合素4介导了ALI中的EC炎症反应，并可能在这种情况下作为一个非常新的治疗靶点。 公共卫生相关性：急性炎症性肺损伤(ALI)是重症监护病房中常见的一个具有挑战性的临床问题，与显著的发病率和死亡率有关。尽管治疗ALI的选择严重有限，但我们之前在ALI动物模型中发现了辛伐他汀的保护作用，辛伐他汀是一种常用的降低血清胆固醇水平的药物，我们随后的基因组研究发现，辛伐他汀治疗后整合素4蛋白显著增加。因此，我们现在假设，整合素4介导了ALI的血管炎症反应，并可能在这种情况下作为一个非常新的治疗靶点。

DESCRIPTION (provided by applicant): Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. A cardinal feature of ALI is an increase in lung vascular permeability, often precipitated by an exuberant inflammatory response with subsequent endothelial barrier disruption. Strategies designed to attenuate vascular permeability could provide attractive novel therapeutic targets and approaches. We previously identified the protective effects of simvastatin, an HMG CoA-reductase inhibitor, in a murine model of ALI and defined potent anti-inflammatory effects of statins including augmentation of endothelial cell (EC) barrier function. Genomic studies of simvastatin-mediated EC gene expression identified the dramatic upregulation of integrin ¿4, a laminin receptor expressed in numerous cell types including EC, suggesting a potentially novel ALI target. While information is limited as to the role of integrin ¿4 in EC, integrins are known to serve as mediators of inflammatory signaling and we have recently confirmed the attenuation of lung inflammation associated with the inhibition of integrin ¿4 in separate models of murine ALI and ventilator-induced lung injury (VILI). Accordingly, we now hypothesize that integrin ¿4 mediates EC inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting. PUBLIC HEALTH RELEVANCE: Acute inflammatory lung injury (ALI) is a challenging clinical problem that is commonly encountered in the intensive care unit and is associated with significant morbidity and mortality. Although treatment options for ALI are severely limited we previously identified the protective effects of simvastatin, a drug commonly used to lower serum cholesterol levels, in an animal model of ALI and our subsequent genomic studies identified the dramatic increase in the protein integrin ¿4 in response to simvastatin treatment. Accordingly, we now hypothesize that integrin ¿4 mediates vascular inflammatory responses in ALI and may serve as a highly novel therapeutic target in this setting.