GASTRIC MUCOSAL INJURY ROLE OF INFLAMMATORY MEDIATORS

炎症介质对胃粘膜损伤的作用

• 批准号: 3227689
• 负责人: LAURENCE Y CHEUNG
• 金额: $ 20.11万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-12-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3227689
• 关键词: dogs; endopeptidases; endotoxins; free radical oxygen; gastric mucosa; gastritis; gastrointestinal agents; gastrointestinal circulation; gastrointestinal circulatory insufficiency; gastrointestinal motility /pressure; gastrointestinal pharmacology; hemostasis; inhibitor /antagonist; leukocyte activation /transformation; microcirculation; monoclonal antibody; multiple organ failure; neurotransmitters; neutrophil; prostaglandin E; radioimmunoassay; radiotracer; thromboxanes; tumor necrosis factor beta; vascular endothelium permeability; vascular resistance; vasoconstriction

Recent studies indicate that the stomach is a target organ injured during sepsis and/or multiple organ failure. Systemic inflammatory mediators released under these conditions may be responsible for gastric microvascular injury, an initiating event in the reduction of mucosal defense against luminal acid. The goal of this application is to examine the role of inflammatory mediators in the pathogenesis of gastric microvascular injury, as evidenced by increased vascular permeability, vasoconstriction, and capillary stasis. Using a canine ex vivo perfused gastric segment as the experimental model, the proposed, studies are designed to: 1) examine the effects of endotoxin, FMLP (formyl-leucyl-methionyl-phenylalanine, a chemotactic peptide released from bacteria), and tumor necrosis factor on the gastric microcirculation. We postulate that the mechanism of microvascular injury by these agents is mainly due to activation of neutrophils, which in turn cause physical obstruction, free radical generation and protease secretion, 2) evaluate the role of gastric hypercontractility in the pathogenesis of gastric microvascular injury. We propose that endotoxin, platelet-activating factor (PAF), and thromboxane A2 stimulate gastric contractions which increase vascular resistance with consequent mucosal ischemia, and 3) assess gastric microvascular injury by these inflammatory mediators released endogenously in an experimental model of intestinal ischemia/reperfusion. The first aim will be achieved by assessing the relationship between activation of neutrophils and changes in gastric vascular resistance, vascular permeability, and filtration during administration of endotoxin, FMLP, and tumor necrosis factor. The effects of these mediators on microvascular injury will also be examined in the absence of circulating neutrophils by using Leukopak filters, which remove 9799% of neutrophils in a single passage. In addition, further studies will examine the significance of neutrophil aggregation, free radical secretion, and adherence to endothelial cells in the mechanism of neutrophil-induced microvascular injury. The second goal will be accomplished by assessing the degree of gastric contractions induced by endotoxin, PAF, and thromboxane A2, and its effect on gastric vascular resistance. The role of various neurotransmitters (i.e., acetylcholine, substance P, serotonin) in gastric contractions stimulated by these mediators will also be examined. The third objective will be pursued by correlating the degree of microvascular injury with inhibitors of endogenously released mediators during intestinal/ischemia reperfusion, including: a) polymyxin B which inactivates endotoxin, b) Leukopak filters, c) BMI 3505, a specific receptor antagonist to thromboxane A2, and d) MoAb #05-106, a monoclonal antibody which binds tumor necrosis factor. These proposed studies will provide new information regarding mechanisms involved in gastric microvascular injury, an initiating event in stress gastritis. Since the stomach is one of the organs adversely affected in patients with sepsis and/or multiple organ failure, a better understanding of gastric microcirculatory changes may be beneficial to our knowledge regarding other organ dysfunctions.

最近的研究表明胃是一个靶器官 在败血症和/或多器官衰竭期间受伤。 全身炎症 在这些条件下释放的介质可能是胃粘膜损伤的原因。 微血管损伤，粘膜损伤减少的起始事件， 对卢米酸的防御 本应用程序的目标是检查 炎症介质在胃癌发病中的作用 微血管损伤，如血管通透性增加所证明的， 血管收缩和毛细血管停滞。 使用离体灌注的犬 胃段作为实验模型，提出，研究 设计用于：1）检查内毒素、FMLP （甲酰基-亮氨酰基-甲硫氨酰基-苯丙氨酸，一种从 细菌）和肿瘤坏死因子对胃微循环的影响。 我们 假设这些药物造成微血管损伤的机制是 这主要是由于中性粒细胞的激活，这反过来又导致身体 阻塞、自由基生成和蛋白酶分泌，2）评估 胃收缩功能亢进在胃癌发病中的作用 微血管损伤 我们认为，内毒素，血小板活化 血小板活化因子（PAF）和血栓素A2刺激胃收缩， 增加血管阻力，随之发生粘膜缺血，和3） 通过这些炎症介质评估胃微血管损伤 在实验性肠梗阻模型中内源性释放 缺血/再灌注 第一个目标将通过评估 中性粒细胞活化与胃血管变化之间的关系 给药期间的阻力、血管通透性和滤过 内毒素、FMLP和肿瘤坏死因子。 这些介质的作用 微血管损伤也将在没有循环的情况下进行检查。 使用Leukopak过滤器去除9799%的中性粒细胞 in a single单passage通道. 此外，进一步的研究将审查 中性粒细胞聚集、自由基分泌和 粘附内皮细胞的机制中的嗜酸性粒细胞诱导的 微血管损伤 第二个目标将通过评估 内毒素、PAF和 血栓素A2及其对胃血管阻力的影响。 的作用 各种神经递质（即，乙酰胆碱、P物质、血清素） 在这些介质刺激的胃收缩中， 考察 第三个目标将通过将程度 微血管损伤与内源性释放介质的抑制剂 在肠/缺血再灌注期间，包括：a）多粘菌素B， 灭活内毒素，B）Leukopak过滤器，c）BMI 3505，特异性 血栓烷A2受体拮抗剂，和d）MoAb#05 - 106，单克隆抗体， 结合肿瘤坏死因子的抗体。 这些拟议的研究将提供新的信息， 胃微血管损伤的机制，一个起始事件 应激性胃炎 由于胃是一个器官不利 在脓毒症和/或多器官衰竭患者中， 了解胃微循环变化可能有助于我们 了解其他器官功能障碍。