GASTROINTESTINAL MICROCIRCULATORY CHANGES DURING SEPSIS

脓毒症期间胃肠道微循环的变化

• 批准号: 2703654
• 负责人: LAURENCE Y CHEUNG
• 金额: $ 7.5万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-12-01 至 1998-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2703654
• 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中受伤 根据这些 在这种情况下，器官因系统释放的 炎症介质和细胞因子。 我们实验室的研究 目前供资期间表明， 白细胞在胃癌的发病机制中起重要作用 由几种炎症介质诱导的微血管损伤（即，巴基斯坦空军， TNF-alpha，FMLP）。 这种微循环损伤包括胃粘膜的变化， 血管阻力增加，血管通透性增加， 对血管活性剂的反应性。 这些研究是在急性 使用炎症介质的外源性给药的实验。 的 对这种应用的拟议研究是我们急性 慢性脓毒症动物模型的研究。 的中心目标 这项应用的拟议研究是检查微血管变化 并确定脓毒症后的潜在机制， 大鼠盲肠结扎-穿刺。 使用活体显微镜， 直接观察循环系统之间的粘附相互作用， 白细胞和肠道微循环， 白细胞依赖性微血管损伤将被更清楚地定义。 在 此外，我们将研究几种潜在的干预措施，以减少 脓毒症时的微血管损伤和器官功能障碍。 利用最近 随着分子生物学的发展，这些干预措施包括：1）预防 通过抑制内毒素或脂多糖 （革兰氏阴性细菌细胞膜的组分），和2）阻断 循环白细胞与血管内皮的粘附。 我们推测，脓毒症期间的微循环变化将是 类似于我们之前使用外源性给药 炎症介质。 此外，活化的白细胞粘附到 血管内皮是微血管损伤的关键步骤 在这种情况下。在上述拟议干预措施中，我们 假设阻断循环白细胞与 血管内皮将具有最大的潜力， 脓毒症时多器官微血管损伤 本申请的拟议研究将提供新的信息 关于白细胞在胃肠道微血管损伤中的作用 在败血症期间。 由于胃肠道是人体的一个器官， 系统的不利影响，在败血症，更好地了解 微循环损伤的病理生理及预防 小肠也应该有益于我们对其他 器官功能失调