Endothelial Barrier Regulation by Simvastatin

描述（由申请人提供）： 肺血管通透性的紊乱，特别是在急性肺损伤（ALI）的情况下，代表了与发病率和死亡率增加明显相关的常见但困难的临床问题，并且目前还没有与ALI相关的血管渗漏的有效疗法。 他汀类药物是一类HMG CoA还原酶抑制剂，由于其降低血脂水平和降低与冠状动脉疾病相关的发病率和死亡率的能力而被临床使用。 然而，并不是所有的有益效果都可以归因于降低胆固醇。 因此，我们假设，通过对内皮细胞（EC）的复杂作用，辛伐他汀诱导屏障保护，并提供了一种新的治疗策略，急性肺损伤（ALI）和呼吸机相关肺损伤（VALI）。 为了支持我们的假设，我们最近报道，辛伐他汀促进内皮细胞（EC）的屏障功能在体外存在的促水肿激动剂，一个具有显着意义的临床条件，特别是血管通透性增加，如ALI/VALI方面的发现。 然而，辛伐他汀增强EC屏障功能的潜在机制仍不清楚，这是K 08申请的主题。 我们已经确定了EC辛伐他汀的双重反应，其特征是明显的早期和延迟效应。 我们现在建议招募一个高度翻译，机制的方法，以进一步研究辛伐他汀对EC的影响。 在具体目标1中，我们将描述辛伐他汀调节EC对凝血酶和TNF-α（临床相关激动剂）以及与VALI相关的周期性伸展反应的特征。 在具体目标2中，我们将探讨时间（早期）EC辛伐他汀的反应与coronin的功能作用，肌动蛋白结合蛋白易位外周辛伐他汀治疗2小时内。 在具体目标3中，我们将研究辛伐他汀对差异EC基因表达的时间（延迟）影响，采用微阵列分析人类和小鼠肺微血管EC，特别关注基因本体，包括细胞骨架成分和调节剂。 最后，在具体目标4中，我们将使用成熟的小鼠模型研究辛伐他汀在ALI/VALI中的潜在治疗作用。 我们提出的研究将进一步了解他汀类药物对内皮细胞的影响，并可能具有深远的临床意义。

DESCRIPTION (provided by applicant): Derangements in lung vascular permeability, particularly in the context of acute lung injury (ALI), represent a common yet difficult clinical problem clearly associated with increased morbidity and mortality and effective therapies for the vascular leak associated with ALI are currently not available. The statins, a class of HMG CoA-reductase inhibitor, are used clinically for their ability to lower serum lipid levels and reduce the morbidity and mortality associated with coronary artery disease. However, not all of their beneficial effects can be attributed to cholesterol lowering. Accordingly, we have hypothesized that via complex effects on endothelial cells (EC), simvastatin induces barrier protection and offers a novel therapeutic strategy for acute lung injury (ALI) and ventilator-associated lung injury (VALI). In support of our hypothesis, we recently reported that simvastatin promotes endothelial cell (EC) barrier function in vitro in the presence of edemagenic agonists, a finding with dramatic significance with respect to clinical conditions characterized specifically by increased vascular permeability such as ALI/VALI. The underlying mechanism by which simvastatin augments EC barrier function, however, remains unclear and is the subject of this K08 application. We have identified a dual EC simvastatin response characterized by distinct early and delayed effects. We now propose to enlist a highly translational, mechanistic approach to further investigate simvastatin effects on EC. In Specific Aim 1, we will characterize simvastatin modulation of EC responses to thrombin and TNF-a, clinically relevant agonists, and to cyclic stretch, relevant to VALI. In Specific Aim 2, we will explore the temporal (early) EC simvastatin response with respect to the functional role of cortactin, an actin-binding protein which translocates peripherally within 2 h of simvastatin treatment. In Specific Aim 3, we will examine the temporal (delayed) effects of simvastatin on differential EC gene expression employing microarray analysis of human and mouse lung microvascular EC with specific focus on gene ontologies including cytoskeletal components and regulators. Finally, in Specific Aim 4, we will use a well-developed mouse model to investigate the potential therapeutic role of simvastatin in ALI/VALI. Our proposed studies will further the current understanding of statin effects on the endothelium and may have profound clinical relevance.