Integrin Beta 4 in Vascular Inflammatory Responses

描述（由申请人提供）：急性炎症性肺损伤（ALI）是重症监护室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的一个主要特征是肺血管通透性增加，通常由过度的炎症反应引起，随后内皮屏障破坏。旨在减弱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。我们先前确定了辛伐他汀（一种HMG CoA还原酶抑制剂）在ALI小鼠模型中的保护作用，并确定了他汀类药物的强效抗炎作用，包括增强内皮细胞（EC）屏障功能。辛伐他汀介导的EC基因表达的基因组学研究发现，整合素4（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）的显著上调，提示了一种潜在的新型ALI靶点。虽然关于整合素4在EC中的作用的信息是有限的，但已知整合素作为炎症信号传导的介质，并且我们最近证实了在小鼠ALI和呼吸机诱导的肺损伤（VILI）的单独模型中与整合素4的抑制相关的肺部炎症的减弱。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高度新颖的治疗靶点。 公共卫生相关性：急性炎症性肺损伤（ALI）是一个具有挑战性的临床问题，是经常遇到的重症监护病房，并与显着的发病率和死亡率。尽管ALI的治疗选择受到严重限制，但我们先前在ALI动物模型中确定了辛伐他汀（一种常用于降低血清胆固醇水平的药物）的保护作用，并且我们随后的基因组研究确定了蛋白整合素4对辛伐他汀治疗的反应显着增加。因此，我们现在假设整合素4介导ALI中的血管炎症反应，并可能在这种情况下作为一个高度新颖的治疗靶点。

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.