Induction of molecular Mediators by Enteral Nutrients in the Postischemic Gut

描述（由申请人提供）：创伤性伤害是导致死亡的主要原因。虽然早期死亡是继发于出血，但晚期死亡可归因于多器官衰竭（MOF）。早期肠内营养与免疫增强营养素（lEN's）的制度已被证明可以降低感染性发病率，从而减少损伤后晚期MOF的发生率。然而，它们在危重患者中的使用受到质疑，因为这类患者的死亡率可能会增加。精氨酸作为一氧化氮的底物，在iNOS被激活的患者中引起伤害。每一种lEN对缺血后肠道的作用机制尚不清楚。虽然我们的数据表明肠内谷氨酰胺可能通过激活PPARgamma对缺血后肠道具有保护作用，但我们也表明精氨酸在相同条件下通过激活一氧化氮以及通过c-jun/ MARK途径选择性激活AP-1（但不是NFKB）是有害的。虽然我们的长期目标是阐明每种IEN调节局部（肠道）和全身炎症反应的机制，但目前的建议将只关注研究谷氨酰胺和精氨酸在缺血后肠道中的局部作用。总的假设是，肠内谷氨酰胺通过激活PPARgamma对缺血后肠道具有保护作用，而肠内精氨酸通过激活iNOS和AP-1具有损伤作用。目的1和2是机制性的，将进一步研究PPARgamma在谷氨酰胺保护作用中的新作用，以及通过一氧化氮介导的蛋白激酶G途径选择性激活AP-1和iNOS在精氨酸损伤作用中的作用。目的3将检查精氨酸和谷氨酰胺联合给药作为同步和补救性治疗给予缺血后肠道的后果。利用啮齿类动物肠道缺血/再灌注模型和氧化应激细胞培养模型以及复杂的分子技术，这些研究将深入了解缺血后肠道基因产物表达的分子机制，以及这些营养物质如何损害或保护肠道。预计本研究将为临床试验的基本原理设计提供基础，以明确在肠道灌流不足期间为重症损伤患者提供最佳肠内营养，从而可能减少损伤后MOF的发生率。

DESCRIPTION (provided by applicant): Traumatic injuries are a leading cause of death. While early deaths are secondary to hemorrhage, late deaths are attributed to multiple organ failure (MOF). The institution of early enteral nutrition with immune enhancing nutrients (lEN's) has been shown to decrease infectious morbidity and therefore lessen the incidence of late post-injury MOF. Their use in critically ill patients, however, has been called into question, as mortality may be increased in this patient population. Arginine, as a substrate for nitric oxide, has been implicated in causing harm in patients in whom iNOS is activated. The mechanisms by which each of the lEN's exert their effect on the postischemic gut is unclear. While our data suggests that enteral glutamine may be protective to the postischemic gut through the activation of PPARgamma, we have also shown that arginine under these same conditions is harmful via activation of nitric oxide as well as through selective activation of AP-1 (but not NFKB) via the c-jun/ MARK pathway. Although our long range goal is to elucidate the mechanisms by which each IEN modulates both the local (gut) and systemic response to inflammation, the current proposal will focus only on investigating the local effects of glutamine and arginine in the post- ischemic gut. The overall hypothesis is that enteral glutamine is protective to the postischemic gut through activation of PPARgamma and that enteral arginine is injurious through activation of iNOS and AP-1. Aim 1 and 2 are mechanistic and will further investigate the novel role of PPARgamma in the protective effect afforded by glutamine and the selective activation of AP-1 and iNOS through the nitric oxide-mediated protein kinase G pathway in the injurious effect of arginine. Aim 3 will examine the consequences of admin- istration of arginine and glutamine in combination when delivered as synchronous and salvage therapy to the postischemic gut. Using a rodent model of gut ischemia/reperfusion and a cell culture model of oxidant stress along with sophisticated molecular techniques, these studies will important insight into the molecular mechanisms governing the expression of gene products expressed in the postischemic gut and how these nutrients harm or protect the gut. It is anticipated this study will provide the basis for the rationale design of clinical trials to specifically address the optimal enteral nutrients for adiministration to critically injured patients during periods of gut hypoperfusion and may therefore lessen the incidence of postinjury MOF.