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目标器官 在败血症和/或多个器官衰竭期间受伤。 系统性炎症 在这些条件下释放的调解人可能是胃的 微血管损伤，粘膜减少的起始事件 防止发光酸的防御。 该应用的目的是检查 炎症介质在胃发病机理中的作用 微血管损伤，血管通透性增加证明了 血管收缩和毛细血管停滞。 使用犬类的体内灌注 胃段作为实验模型，提出的研究是 设计为：1）检查内毒素FMLP的影响 （甲基 - 核基 - 甲基 - 苯基丙氨酸，一种从脱趋化肽 细菌），胃微循环中的肿瘤坏死因子。 我们 假设这些药物的微血管损伤机制是 主要是由于中性粒细胞的激活，这又导致物理 障碍物，自由基发电和蛋白酶分泌，2）评估 胃超额收缩在胃发病机理中的作用 微血管损伤。 我们提出了内毒素，血小板激活 因子（PAF）和血栓烷A2刺激胃收缩 增加血管耐药性，从而增加粘膜缺血，3） 评估这些炎症介质的胃微血管损伤 在肠道模型中内源性释放 缺血/再灌注。 第一个目标将通过评估关系来实现 中性粒细胞的激活与胃血管的变化之间 给药期间的抗性，血管渗透性和过滤 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，还将检查微血管损伤 中性粒细胞使用白细胞过滤器，该过滤器去除9799％的中性粒细胞 在一次段落中。 此外，进一步的研究将研究 中性粒细胞聚集，自由基分泌和 在中性粒细胞诱导的机理中遵守内皮细胞 微血管损伤。 第二个目标将通过评估来实现 内毒素，PAF和 血栓烷A2及其对胃血管抗性的影响。 角色 各种神经递质（即乙酰胆碱，物质P，5-羟色胺）的 在这些调解人刺激的胃收缩中也将是 检查。 第三个目标将通过关联学位来追求 内源释放介质的抑制剂微血管损伤 在肠道/缺血再灌注期间，包括：a）多粘蛋白B 灭活性内毒素，b）leukopak滤波器，c）BMI 3505，一种特定 对血栓烷A2的受体拮抗剂和D）Moab＃05-106，单克隆 结合肿瘤坏死因子的抗体。 这些拟议的研究将提供有关有关的新信息 胃微血管损伤涉及的机制，这是一个引发事件 在压力胃炎中。 由于胃是不利的器官之一 在患有败血症和/或多器官衰竭的患者中受到影响，更好 了解胃微循环变化可能对我们有益 有关其他器官功能障碍的知识。