Regulation of sinusoidal perfusion in shock

肝脏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， 这与内皮素缩血管反应增强有关，而内皮型一氧化氮合酶则减少。 激活。我们现在假设炎症和氧化应激与休克和脓毒症有关 通过对滞留在小窝中的蛋白质的影响来干扰内皮素-1的信号传递。其结果是解偶联 ET受体来自eNOS的激活，而不是来自收缩信号。最终导致血管调节失调 增强肝脏损伤和炎症反应。考虑到许多信号分子是 被隔离在小窝中，这项研究的潜在意义超出了血管调节。 并可能对休克和脓毒症期间细胞信号的一般情况提供有价值的见解。为了 为了验证这一假设，我们提出了以下目标。目标1：测试蛋白质的改变是否与 合并小凹是休克相关损伤的常见途径。目标2：测试基础数据是否发生变化 小窝相关蛋白的表达导致内皮素-1信号的改变。目标3：测试是否 应激诱导的变化可以通过操纵腔泡域的成分来模拟。目标4： 测试目标1-3中确定的重要机制的操作是否对 体内血管调节、组织氧分布与肝损伤。在完成上述目标后， 我们将阐明典型的体外应激和临床相关的活体应激的影响。 影响内皮素和血管活性物质相互作用的空泡结构域相关蛋白的调节 不是的。我们还将确定这些变化对内皮素信号转导的功能意义。 体外和体内对肝脏血管的调节作用。肝脏微循环有许多独特的方面； 然而，有证据表明，经过一些修改后，这些机制实际上可能在 血管细胞。因此，我们的发现可能会有比仅仅了解肝脏更广泛的应用 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.