Induction of molecular Mediators by Enteral Nutrients in the Postischemic Gut

描述（由申请人提供）：外伤是死亡的主要原因。早期死亡是继发于出血，而晚期死亡则归因于多器官衰竭（MOF）。已证明采用免疫增强营养素 (lEN) 进行早期肠内营养可以降低感染发病率，从而减少晚期损伤后 MOF 的发生率。然而，它们在重症患者中的使用受到了质疑，因为该患者群体的死亡率可能会增加。精氨酸作为一氧化氮的底物，可能会对 iNOS 被激活的患者造成伤害。每种 IEN 对缺血后肠道发挥作用的机制尚不清楚。虽然我们的数据表明肠内谷氨酰胺可能通过激活 PPARgamma 对缺血后肠道起到保护作用，但我们也表明，在这些相同条件下，精氨酸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。尽管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，但目前的提案将仅侧重于研究谷氨酰胺和精氨酸在缺血后肠道中的局部影响。总体假设是肠内谷氨酰胺通过激活 PPARgamma 对缺血后肠道起到保护作用，而肠内精氨酸通过激活 iNOS 和 AP-1 有害。目标 1 和 2 是机制性的，将进一步研究 PPARgamma 在谷氨酰胺提供的保护作用中的新作用，以及在精氨酸的损伤作用中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。目标 3 将检查精氨酸和谷氨酰胺联合给药作为缺血后肠道同步和挽救治疗的后果。使用肠道缺血/再灌注的啮齿动物模型和氧化应激的细胞培养模型以及复杂的分子技术，这些研究将重要地深入了解控制缺血后肠道中表达的基因产物的表达的分子机制以及这些营养素如何伤害或保护肠道。预计这项研究将为临床试验的合理设计提供基础，以专门解决肠道低灌注期间危重患者的最佳肠内营养给药问题，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.