Prostanoids and Liver Microcirculation in Stresses

描述（由申请人提供）： 内毒素血症是肝硬化常见而严重的并发症，常引起肝损伤甚至器官衰竭。然而，在连续应激中，硬化性肝脏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，在动脉硬化的肝脏中，收缩性内皮素（ET）的肝脏上调和血管扩张性一氧化氮（NO）的释放减少。我们的初步研究表明，在肝硬化，收缩前列腺素类释放响应ET，和前列腺素类的作用是调制NO。我们还表明，内毒素血症作为一种继发性应激引起了额外的上调已经增加ET基因的表达在肝硬化大鼠的肝脏，但内毒素诱导的诱导型一氧化氮合酶的表达被钝化的预先存在的肝硬化。因此，我们假设，肝硬化作为一个预先存在的条件引发的肝微循环的易感性之间的不平衡收缩和扩张的影响，通过敏感的ET/收缩前列腺素途径和减少生产的NO。我们进一步假设，内毒素血症作为一个次要的压力进一步激活的途径，导致失调的肝微循环，并最终肝细胞损伤。为了验证这些假设，提出了三个具体的目标：1）确定肝硬化作为一种预先存在的疾病是否通过使ET介导的血管收缩剂前列腺素类的释放敏感化而使肝脏微循环对收缩剂和扩张剂影响之间的不平衡的易感性做好准备; 2）确定作为二次应激的内毒素血症是否增强由血管收缩剂前列腺素类的释放介导的升压反应以响应ET; 3）确定ET的压倒性增加是否伴随着ET诱导的前列腺素类释放的增敏以及在连续应激后iNOS表达的减弱导致血管收缩和血管舒张的不平衡调节以及肝微循环的失调。这一建议不仅将使我们能够评估收缩前列腺素类在肝硬化和内毒素诱导的顺序应激中对肝微循环的调节作用，而且还将为双重应激条件下预防肝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.