MEDIATORS OF INTESTINAL ISCHEMIA

由于血管闭塞、血管痉挛或慢性 炎症是一种主要的胃肠道疾病， 发病率很高，约占该国死亡人数的4%。 虽然许多工作已经致力于肠缺血性疾病， 关于参与的基本机制知之甚少， 疾病的发病机制。 此外，临床诊断肠 局部缺血可能被遗漏或在缺血的不可逆阶段被发现。 导致大量肠组织切除的疾病。 因为小 同种异体肠移植可能是一种可行的治疗方法，在这些情况下， 并需要适当的保护策略，科学的 肠缺血与低温肠探讨 保护是必要的。 该提案探讨了地方政府的作用， 炎症介质在肠缺血中的作用 通过生化生理学和药理学研究肠道功能 问题研究 此外，肠组织产生的脂质介质 进行低温保存和随后的再灌注 （自体移植）进行了研究。 密切监测肠道 功能（营养吸收，血液流动，微循环）将允许 阐明功能紊乱以及 药物干预肠组织受到温暖 缺血再灌注损伤和冷缺血再灌注损伤 （低温保存）。 犬肠缺血再灌注模型的建立 损伤和肠器官保存。 花生四烯酸代谢 并阐明了血小板活化因子（PAF）的产生（免疫学 和GC/MS测定），同时在这些模型中进行肠功能 研究（营养吸收和循环调节），并与 从正常肠组织获得的值。 有毒物质的积累 监测低温和常温缺血期间的酰基辅酶A酯 采用HPLC 粘膜代谢的体外测定（腺嘌呤， 核苷酸，02，谷胱甘肽）在低温缺血期间测定 有和没有实验性的保存溶液和技术。 常温和低温期间肠道中性粒细胞浸润。 通过组织髓过氧化物酶含量监测局部缺血。 预计 类花生酸、血小板活化因子和其他脂质代谢物的显著变化 肠组织在缺血再灌注损伤过程中将与 功能衰退 此外，合理的药物干预， 花生四烯酸代谢、PAF合成、氧自由基和脂质 酰基辅酶A酯在温暖和寒冷期间应保持肠道功能 缺血 这项建议是对病理生理学的广泛调查， 严重肠缺血的机制和一项旨在探索 肠缺血再灌注损伤的局部机制。

Intestinal ischemia due to vascular occlusion, vasospasm, or chronic inflammation is a major gastrointestinal disorder that results in significant morbidity and accounts for about 4% of deaths in this country. Although much work has been devoted to intestinal ischemic disorders, little is known about the underlying mechanisms involved in the pathogenesis of the disease. Furthermore, clinical diagnosis of intestinal ischemia may be missed or discovered at an irreversible stage of the disease resulting in massive resection of intestinal tissue. Since small intestinal allotransplantation could be a viable therapy in these settings and would require adequate preservation strategies, scientific investigation into intestinal ischemia and hypothermic intestinal preservation is warranted. This proposal investigates the role of local inflammatory mediators in intestinal ischemia and their effects on intestinal function through biochemical physiologic, and pharmacologic studies. Also, the production of lipid mediators by intestinal tissue subjected to hypothermic preservation and subsequent reperfusion (autotransplantation) is investigated. Close monitoring of intestinal function (nutrient absorption, blood flow, microcirculation) will allow elucidation of the functional derangements as well as possible benefits of pharmacologic intervention in intestinal tissue subjected to warm ischemia-reperfusion injury and cold ischemia-reperfusion injury (hypothermic preservation). A dog model of intestinal ischemia-reperfusion injury and intestinal organ preservation is used. Arachidonate metabolism and Platelet Activation Factor (PAF) production is elucidated (immunologic and GC/MS assays) in these models concurrent with intestinal functional studies (nutrient absorption and circulatory regulation) and compared to values obtained from normal intestinal tissue. The accumulation of toxic acyl-CoA esters during hypothermic and normothermic ischemia is monitored by HPLC. In-vitro determinations of mucosal metabolism (adenine, nucleotides, 02, glutathione) is determined during hypothermic ischemia with and without experimental preservation solutions and techniques. Intestinal neutrophil infiltration during normothermic and hypothermic . ischemia is monitored by tissue myeloperoxidase content. It is anticipated that dramatic alterations in eicosanoids, PAF, and other lipid metabolites by intestinal tissue during ischemia-reperfusion injury will correlate with functional decline. Also, rational pharmacologic intervention directed at arachidonate metabolism, PAF synthesis, oxygen free radicals, and lipid acyl-CoA esters should preserve intestinal function during warm and cold ischemia. This proposal is a broad investigation into the pathophysiologic mechanisms of severe intestinal ischemia and a study directed at exploring the local mechanisms of intestinal preservation-reperfusion injury.