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，胃是靶器官。 败血症和/或多器官衰竭时受伤。全身性炎症 在这些条件下释放的介质可能对胃病负责 微血管损伤--粘膜减少的始动事件 对鲁米那酸的防御。此应用程序的目标是检查 炎症介质在胃病发病中的作用 微血管损伤，表现为血管通透性增加， 血管收缩和毛细血管停滞。使用体外灌流的犬类 以胃段为实验模型，提出，研究内容如下 旨在：1)检查内毒素、FMLP的影响 (甲酰-亮氨酰-甲硫基-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 假设这些药物对微血管的损伤机制是 主要是由于中性粒细胞的激活，进而导致物理 梗阻、自由基生成和蛋白酶分泌，2)评估 胃收缩功能亢进在胃病发病中的作用 微血管损伤。我们认为内毒素、血小板活化 因子(PAF)和血栓素A2刺激胃收缩， 血管阻力增加，继而发生粘膜缺血，以及3) 这些炎性介质对胃微血管损伤的评估 大鼠肠道内源性释放的实验模型 缺血/再灌流。 第一个目标将通过评估两国关系来实现 中性粒细胞激活与胃血管变化的关系 给药期间的阻力、血管通透性和滤过性 内毒素、FMLP和肿瘤坏死因子。这些调解人的影响 在没有循环的情况下也会检查微血管损伤 使用Leukopak过滤器，可去除9799%的中性粒细胞 在一段时间里。此外，进一步的研究将审查 中性粒细胞聚集、自由基分泌及 中性粒细胞诱导的内皮细胞黏附机制 微血管损伤。第二个目标将通过评估来实现 内毒素、纤溶酶原激活物、胃动素引起的胃收缩程度 血栓素A2及其对胃血管阻力的影响角色 各种神经递质(如乙酰胆碱、P物质、5-羟色胺) 在这些介质刺激的胃收缩中也会 检查过了。第三个目标将通过关联学位来实现 内源性释放介质抑制物对微血管损伤的影响 在肠/缺血再灌注期间，包括：A)多粘菌素B 灭活内毒素，b)白血球过滤器，c)BMI 3505，一种特定的 血栓烷A2的受体拮抗剂，以及d)单抗#05-106，单抗 与肿瘤坏死因子结合的抗体。 这些拟议的研究将提供以下方面的新信息 胃微血管损伤的机制--一种启动事件 在应激性胃炎中。因为胃是不利的器官之一 在感染脓毒症和/或多器官衰竭的患者中， 了解胃微循环的变化可能对我们的 关于其他器官功能障碍的知识。