GASTROINTESTINAL MICROCIRCULATORY CHANGES DURING SEPSIS

脓毒症期间胃肠道微循环的变化

• 批准号: 2016021
• 负责人: LAURENCE Y CHEUNG
• 金额: $ 23.43万
• 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 2001-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2016021
• 关键词: bacterial disease; bacterial proteins; blood toxicology; disease /disorder etiology; disease /disorder model; endotoxins; free radical oxygen; gastrointestinal circulation; gene expression; intravital microscopy; laboratory rat; leukocyte adhesion molecules; lipopolysaccharides; mesenteric artery; microcirculation; microfilaments; monoclonal antibody; myeloperoxidase; septic shock; ultrasound blood flow measurement; vascular endothelium permeability; vascular resistance; vasoconstrictors; vasodilation; vasodilators

Recent studies indicate that the stomach and intestine are target organs injured during sepsis-induced multiple organ failure. Under these conditions, organs are injured in response to systemically-released inflammatory mediators and cytokines. Studies from our laboratory during the current funding period have shown that activation of circulating leukocytes plays an important role in the pathogenesis of gastric microvascular injury induced by several inflammatory mediators (i.e., PAF, TNF-alpha, FMLP). This microcirculatory injury includes changes in gastric vascular resistance, increased vascular permeability, and altered vascular reactivity to vasoactive agents. These studies were performed in acute experiments using exogenous administration of inflammatory mediators. The proposed studies of this application are a natural extension of our acute studies to a chronic animal model of sepsis. The central goal of the proposed studies of this application is to examine microvascular changes and to identify the underlying mechanisms following sepsis produced by cecal ligation-puncture in rats. Using intravital microcopy which provides a direct visualization of adhesive interactions between circulating leukocytes and the intestinal microcirculation, the mechanisms of leukocyte-dependent microvascular injury will be more clearly defined. In addition, we will examine several potential interventions to reduce microvascular injury and organ dysfunction during sepsis. Utilizing recent advances in molecular biology, these interventions include: 1) prevention of host immune responses by inhibition of endotoxin or lipopolysaccharide (a component of gram negative bacterial cell membrane), and 2) blockade of adhesion of circulating leukocytes with vascular endothelium. We postulate that the microcirculatory changes during sepsis will be similar to our previous observations using exogenously administered inflammatory mediators. Furthermore, adhesion of activated leukocytes to vascular endothelium represents a critical step in microvascular injury under these conditions. Of the proposed interventions described above, we hypothesize that blockade of adhesion of circulating leukocytes with vascular endothelium will have the greatest potential in reducing microvascular injury in multiple organs during sepsis. The proposed studies of this application will provide new information regarding the role of leukocytes in gastrointestinal microvasculalr injury during sepsis. Since the gastrointestinal tract is one of the organ systems adversely affected during sepsis, a better understanding of the pathophysiology and the prevention of the microcirculatory injury in the small intestine should also be beneficial to our knowledge regarding other organ dysfunctions under these conditions.

最近的研究表明，胃和肠是靶器官 在脓毒症引起的多器官衰竭期间受伤。 在这些之下 在某些情况下，器官会因系统释放的物质而受伤 炎症介质和细胞因子。 我们实验室的研究 当前的资助期表明，流通的激活 白细胞在胃病的发病机制中发挥着重要作用 多种炎症介质（即 PAF、 TNF-α、FMLP）。 这种微循环损伤包括胃功能的改变 血管阻力、血管通透性增加、血管改变 对血管活性药物的反应性。 这些研究是在急性 使用外源性施用炎症介质的实验。 这 该应用程序的拟议研究是我们敏锐的自然延伸 对脓毒症慢性动物模型的研究。 该组织的中心目标是 该应用的拟议研究是检查微血管变化 并确定脓毒症产生的潜在机制 大鼠盲肠结扎穿刺。 使用活体显微镜检查可提供 循环之间粘附相互作用的直接可视化 白细胞与肠道微循环的机制 白细胞依赖性微血管损伤将得到更明确的定义。 在 此外，我们将研究几种潜在的干预措施，以减少 脓毒症期间的微血管损伤和器官功能障碍。 利用最近的 随着分子生物学的进步，这些干预措施包括：1）预防 通过抑制内毒素或脂多糖来调节宿主免疫反应 （革兰氏阴性细菌细胞膜的一个组成部分），以及 2) 阻断 循环白细胞与血管内皮的粘附。 我们假设败血症期间的微循环变化 与我们之前使用外源给药的观察结果相似 炎症介质。 此外，活化的白细胞粘附 血管内皮是微血管损伤的关键一步 在这些条件下。在上述建议的干预措施中，我们 假设阻断循环白细胞的粘附 血管内皮细胞在减少 脓毒症期间多个器官的微血管损伤。 该应用程序的拟议研究将提供新信息 白细胞在胃肠道微血管损伤中的作用 败血症期间。 由于胃肠道是人体器官之一 脓毒症期间系统受到不利影响，更好地了解 微循环损伤的病理生理学和预防 小肠也应该有利于我们了解其他方面的知识 在这些条件下器官功能障碍。