Prostanoids and Liver Microcirculation in Stresses

描述(由申请人提供)： 内毒素血症是肝硬变常见而严重的并发症，常导致肝脏损伤甚至器官衰竭。然而，在连续的应激中，肝硬变对内毒素血症的易感性增加的机制还不完全清楚。研究表明，在肝硬变过程中，肝脏收缩内皮素(ET)上调，血管扩张剂一氧化氮(NO)释放减少。我们的初步研究表明，在肝硬变中，收缩前列腺素是对ET的反应而释放的，而前列腺素的作用受NO的调节。我们还发现，内毒素血症作为一种继发性应激，在肝硬变大鼠肝脏中引起了已经增加的ET基因表达的额外上调，但内毒素诱导的诱导型一氧化氮合酶的表达被先前存在的肝硬变钝化。因此，我们假设肝硬变作为一种预先存在的状态，通过敏化ET/收缩前列腺素途径和减少NO的产生，使肝脏微循环容易受到收缩和扩张之间的失衡的影响。我们进一步假设，内毒素血症作为一种继发性应激，进一步激活了导致肝脏微循环失调并最终导致肝细胞损伤的途径。为了验证这些假说，我们提出了三个具体目标：1)确定作为既往疾病的肝硬变是否通过敏化ET介导的血管收缩前列腺素的释放而使肝脏微循环容易受到收缩和扩张之间的失衡影响；2)确定作为二次应激的内毒素血症是否增强了由血管收缩前列腺素的释放介导的升压反应；3)确定ET的压倒性升高是否伴随着ET诱导的前列腺素释放的敏化以及顺序应激后iNOS的表达减弱是否导致血管收缩和血管扩张的失衡调节以及肝脏微循环的调节失调。这一建议不仅将使我们能够评估收缩前列腺素在肝硬变和内毒素诱导的顺序应激中对肝脏微循环的调节作用，而且将为在双重应激条件下预防肝脏微循环衰竭的治疗策略提供宝贵的信息。

DESCRIPTION (provided by applicant): Endotoxemia is a common but severe complication of cirrhosis frequently causing liver injury and even organ failure. The mechanism underlying the increased susceptibility of the cirrhotic liver to endotoxemia in the sequential stresses, however, is not completely understood. Studies have shown a hepatic upregulation of constrictor endothelin (ET) and a decreased release of vasodilator nitric oxide (NO) in the cirrhotic liver. Our preliminary studies have shown that in cirrhosis, constrictor prostanoids are released in response to ET, and the action of the prostanoids is modulated by NO. We also showed that endotoxemia as a secondary stress caused an additional upregulation in already increased ET gene expression in the cirrhotic rat liver, but endotoxin-induced expression of inducible nitric oxide synthase was blunted by the preexisting cirrhosis. We therefore hypothesize that liver cirrhosis as a pre-existing condition primes the hepatic microcirculation for predisposition to an imbalance between constrictor and dilator influences by sensitizing the ET/constrictor prostanoids pathway and decreasing production of NO. We further hypothesize that endotoxemia as a secondary stress further activates the pathway leading to dysregulation of the hepatic microcirculation and ultimately hepatocellular injury. To test these hypotheses, three specific aims are proposed: 1) determine whether cirrhosis as a pre-existing condition primes the hepatic microcirculation for predisposition of an imbalance between constrictor and dilator influences by sensitizing the ET-mediated release of vasoconstrictor prostanoids; 2) determine whether endotoxemia as a secondary stress enhances the pressor response mediated by the release of vasoconstrictor prostanoids in response to ET; 3) determine whether an overwhelming increase in ET accompanied by the sensitization of ET-induced release of prostanoids and an attenuated expression in iNOS following the sequential stresses result in an imbalanced regulation of vasoconstriction and vasodilation and dysregulation of the hepatic microcirculation. This proposal not only will allow us to evaluate the role of constrictor prostanoids in regulation of hepatic microcirculation in cirrhosis and endotoxin-induced sequential stresses, but also will provide invaluable information on therapeutic strategies to prevent hepatic microcirculatory failure under the double stressed conditions.