? 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. ? ?
