Induction of molecular Mediators by Enteral Nutrients in the Postischemic Gut

缺血后肠道肠内营养物诱导分子介质

• 批准号: 7641116
• 负责人: Rosemary A Kozar
• 金额: $ 28.22万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-01 至 2012-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7641116
• 关键词: Address; Age; Agonist; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Arginine; Cause of Death; Cell Culture Techniques; Cessation of life; Clinical Trials; Clinical Trials Design; Combined Modality Therapy; Critical Illness; Cyclic GMP-Dependent Protein Kinases; Data; Diet; Enteral; Enteral Nutrition; Enterocytes; Epithelial; Functional disorder; Glutamine; Goals; Heat shock proteins; Hemorrhage; Immune; In Vitro; Incidence; Inflammation; Inflammation Mediators; Inflammatory disease of the intestine; Injury; Institution; Intestines; Ischemia; JUN gene; Ligands; Mediating; Mediator of activation protein; Mesentery; Modeling; Molecular; Morbidity - disease rate; Multiple Organ Failure; NF-kappa B; Nitric Oxide; Nucleotides; Nutrient; Nutritional; Omega-3 Fatty Acids; Outcome; Oxidants; PPAR gamma; Pathway interactions; Patients; Perfusion; Peroxisome Proliferator-Activated Receptors; Production; Proteins; Randomized Clinical Trials; Reperfusion Therapy; Research Personnel; Rodent Model; Role; Rosemary; Salvage Therapy; Secondary to; Techniques; Testing; Time; Transcription Factor AP-1; base; clinically relevant; glycosylation; improved; in vivo; injured; insight; mortality; novel; oxidant stress; patient population; programs; prospective; protective effect; response; septic

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.

描述（由申请人提供）：创伤性伤害是死亡的主要原因。虽然早期死亡是出血的继发性死亡，但晚期死亡归因于多器官衰竭（MOF）。已证明具有免疫增强营养（LEN）的早期肠内营养构造可以降低感染性发病率，因此减少了后期伤害后MOF的发生率。但是，由于该患者人群的死亡率可能会增加，因此他们在重病患者中的使用受到质疑。精氨酸作为一氧化氮的底物，已与激活iNOS的患者造成伤害。每个Len对肠道后肠道的影响的机制尚不清楚。尽管我们的数据表明，肠谷氨酰胺可以通过激活Ppargamma来保护肠道后的肠道，但我们还表明，在这种相同条件下的精氨酸通过激活一氧化氮而有害，并且通过选择性激活AP-1（而不是NFKB）通过C-Jun/ Mark途径有害。尽管我们的远距离目标是阐明每个IEN调节局部（肠道）和对炎症的全身反应的机制，但当前的建议将仅着重于研究谷氨酰胺和精氨酸在后缺血性肠道中的局部影响。总体假设是，肠内谷氨酰胺通过激活ppargamma可以保护肠道后的肠道，并且肠氨酸通过激活INOS和AP-1而受到伤害。 AIM 1和2是机械的，将进一步研究PPARGAMMA在谷氨酰胺提供的保护作用中的新作用，以及通过一氧化氮介导的蛋白激酶G途径在精氨酸的损伤作用中对AP-1和INOS的选择性激活。 AIM 3将检查精氨酸和谷氨酰胺的施用后，当将精氨酸和谷氨酰胺组合起来时，将其作为同步和救助疗法提供给缺血后的肠道。这些研究使用肠道性缺血/再灌注的啮齿动物模型以及氧化应激的细胞培养模型以及复杂的分子技术，这些研究将重要的洞察力深入了解，这些分子机制介绍了在肠道后肠道中表达的基因产物表达的分子机制，以及这些养分如何伤害或保护肠道。预计这项研究将为临床试验的基本原理设计提供基础，以专门解决在肠道灌注不良期间对严重受伤的患者进行审查的最佳肠内营养素，因此可能会降低伤后MOF的发生率。