MEDIATORS OF INTESTINAL ISCHEMIA

血管闭塞、血管痉挛或慢性引起的肠缺血 炎症是一种主要的胃肠道疾病，导致 发病率很高，约占该国死亡人数的4%。 尽管已有大量研究致力于肠道缺血性疾病， 对涉及到的潜在机制知之甚少 疾病的发病机制。此外，肠道疾病的临床诊断 缺血可能被遗漏或在不可逆的阶段被发现 导致大量切除肠道组织的疾病。从小到小 在这些环境下，同种异体肠道移植可能是一种可行的治疗方法。 并需要适当的保存策略，科学的 肠缺血和低温肠病的研究进展 保护是有必要的。这项提案调查了地方政府的作用 炎性介质在肠缺血中的作用及其对机体的影响 肠道功能的生化、生理学和药理学研究 学习。此外，肠道组织产生的脂质介体 接受低温保存和随后的再灌注 (自体移植)。密切监测肠道 功能(营养吸收、血液流动、微循环)将允许 阐明功能性错位及其可能的益处 温热条件下肠道组织的药物干预 缺血再灌注损伤与冷缺血再灌注损伤 (低温保存)。犬肠缺血再灌注模型的建立 使用了损伤和肠道器官保存。花生四烯酸代谢 和血小板激活因子(PAF)的产生被阐明(免疫学 和GC/MS分析)在这些模型中同时存在肠道功能 研究(营养吸收和循环调节)，并与 取自正常肠道组织的数值。有毒物质的堆积 监测低温和常温缺血期间的酰基辅酶A酯 用高效液相色谱法测定。粘膜代谢的体外测定(腺嘌呤， 核苷酸，02，谷胱甘肽)在低温缺血期间被测定 有和没有实验保存解决方案和技术。 常温和低温时肠内中性粒细胞的浸润。 通过组织髓过氧化物酶含量监测缺血情况。这是意料之中的 二十烷类化合物、PAF和其他脂质代谢物的戏剧性变化 肠组织在缺血再灌注损伤中的作用 功能衰退。此外，合理的药物干预针对 花生四烯酸代谢、PAF合成、氧自由基和脂质 酰基辅酶A酯应在冷暖条件下保持肠道功能 缺血症。这项建议是对病理生理学的广泛调查。 严重肠缺血的发病机制及探索性研究 肠保存-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.