Regulation of sinusoidal perfusion in shock

肝血管调节改变是休克或脓毒症后的常见事件。最近的研究表明， 这与收缩肌对内皮素的反应增加有关，内皮素与eNOS减少有关 activation.我们现在假设与休克和败血症相关的炎症和氧化应激 通过作用于被隔离在小窝中的蛋白质来破坏内皮素-1的信号传导。其结果是解偶联的 ET受体来自eNOS激活，但不是来自收缩信号。最终血管失调 增强肝损伤和炎症反应。考虑到许多信号分子 在小窝中，这项研究的潜在意义超出了血管调节 并且可以提供关于休克和脓毒症期间细胞信号传导的有价值的见解。为了 为了验证这一假设，我们提出以下目标。目的1：检测蛋白质的改变是否与 是休克相关损伤的常见途径。目的2：检测基础胰岛素水平是否发生变化 小窝相关蛋白的表达导致内皮素-1信号传导的改变。目标3：测试是否 应激诱导的变化可以通过操纵小窝结构域的组分来模拟。目标4： 测试目标1-3中确定为重要的机制的操作是否对 体内血管调节、组织氧分布和肝损伤。在完成上述目标后， 我们将阐明原型体外应力以及临床相关体内应力的影响 调节与小窝结构域相关的蛋白质，影响内皮素和 号我们还将确定这些变化对内皮素信号传导的功能意义， 体外和体内肝血管调节。肝脏微循环有许多独特的方面; 然而，有证据表明，这些机制与一些修改可能实际上是普遍存在的， 血管细胞因此，我们的发现可能有更广泛的应用，而不仅仅是了解肝脏 休克状态下的损伤。

Altered hepatic vascular regulation is a common event following shock or sepsis. Recent work shows that this is related to increased constrictor response to endothelin that is associated with decreased eNOS activation. We now hypothesize that inflammatory and oxidative stress associated with shock and sepsis disrupt signaling of endothelin-1 via effects on proteins sequestered in caveolae. The result is uncoupling of ET receptors from eNOS activation, but not from constrictor signaling. Ultimately vascular dysregulation potentiates liver injury and inflammatory response. Given the many signaling molecules that are sequestered in the caveolae, the potential significance of this investigation goes beyond vascular regulation and may provide valuable insights regarding cell signaling in general during shock and sepsis. In order to test this hypothesis, we propose the following aims. Aim 1: Test whether alterations in proteins associated with caveolae is a common pathway in shock related injuries. Aim 2: Test whether changes in basal expression of caveolae-associated proteins result in altered endothelin-1 signaling. Aim 3: Test whether stress-induced changes can be mimicked by manipulation of components of the caveolar domains. Aim 4: Test whether manipulation of mechanisms identified as important in aims 1-3 have a significant impact on vascular regulation, distribution of tissue oxygen and liver injury in vivo. Upon completion of the above aims, we will have elucidated the effect of prototypical in vitro stresses as well as clinically relevant in vivo stresses on regulation of proteins associated with caveolar domains that affect the interaction between endothelin and NO. We will also have determined the functional significance of these changes for endothelin signaling in vitro and for hepatic vascular regulation in vivo. The hepatic microcirculation has many unique aspects; however, there is evidence that these mechanisms with some modifications may be virtually ubiquitous in vascular cells. Thus our findings are likely to have much broader application than just understanding of liver injury during shock states.