Multiple organ failure (MOF) is a serious, often fatal sequelae of visceral ischemia, resuscitation after severe hemorrhage, sepsis, or following traumatic injury. The overall long term goal of this proposal is to elucidate the humoral factors that contribute to the regulation of splanchnic blood flow during hemorrhage/reperfusion injury. The endogenous humoral factors that contribute to splanchnic blood flow that will be studied include vasoactive eicosanoids and nitric oxide (NO). The exogenous humoral factors investigated include platelet derived vasoconstrictors and oxygen-derived free radicals (ODFRs) formed during hemorrhage/reperfusion injury. Our long term goal is to investigate the specific mechanisms involved in the regulation of the enzymes responsible for eicosanoid and nitric oxide synthesis and degradation during shock states which will contribute to the development of treatment strategies designed to maintain splanchnic blood flow and visceral function following shock. Acute hemorrhage followed by reperfusion will be used either as a primary injury or as an initial injury followed by a second insult to examine the following specific aims: 1) To determine the role of ODFRs on splanchnic eicosanoid synthesis and NO synthesis following early hemorrhagic shock and reperfusion; 2) to determine the role of ODFR on the regulation of splanchnic blood flow following hemorrhagic shock and reperfusion; 3) To determine the role of local platelet eicosanoid and serotonin release in the splanchnic vascular bed following hemorrhagic shock and reperfusion; 4) To determine the role of a second trauma (endotoxin shock, hemorrhage) on splanchnic eicosanoid and NO synthesis and splanchnic blood flow following initial hemorrhagic shock. This proposal will utilize several strategies to determine the role of ODFRs on splanchnic eicosanoid and NO synthesis and splanchnic blood flow during shock. The first strategy will examine the effects of hemorrhage/reperfusion injury on splanchnic eicosanoid and nitric oxide synthesis and release. These studies will determine the location and molecular mechanisms involved with the regulation of the enzymes responsible for splanchnic eicosanoid and nitric oxide synthesis during hemorrhage/reperfusion injury. The second strategy is to examine the effects of ODFRs on splanchnic blood flow following hemorrhage/reperfusion injury. The third strategy is to examine the contribution of platelets to splanchnic vasoconstriction during hemorrhage/reperfusion by release of serotonin and thromboxane. The fourth strategy is to determine the effect of a second trauma (hemorrhage, endotoxin, morphine etc.) on the splanchnic eicosanoid and nitric oxide synthesis and splanchnic blood flow following initial hemorrhage.
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