GASTROINTESTINAL MICROCIRCULATORY CHANGES DURING SEPSIS

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。在这些下面 条件下，器官损伤是对全身释放的反应 炎症介质和细胞因子。来自我们实验室的研究在 本供资期间已表明启动了循环 白细胞在胃病发病机制中的重要作用 几种炎性介质(即PAF， 肿瘤坏死因子-α，FMLP)。这种微循环损伤包括胃部的变化。 血管阻力、血管通透性增加和血管改变 对血管活性物质的反应性。这些研究是在急性发作时进行的 使用外源性炎症介质的实验。这个 对这一应用的拟议研究是我们的 慢性脓毒症动物模型的研究。该计划的中心目标 这一应用的拟议研究是检查微血管的变化。 并找出导致脓毒症的潜在机制 盲肠结扎-穿刺法。使用活体显微镜可以提供 循环间黏附相互作用的直观可视化 白细胞与肠道微循环，其作用机制 白细胞依赖性微血管损伤将得到更明确的定义。在……里面 此外，我们将研究几种潜在的干预措施，以减少 脓毒症时微血管损伤和器官功能障碍。利用最近的 分子生物学的进展，这些干预措施包括：1)预防 抑制内毒素或内毒素引起的宿主免疫反应 (革兰氏阴性细菌细胞膜的成分)，以及2)阻断 循环白细胞与血管内皮细胞的黏附。 我们推测脓毒症期间微循环的变化将是 类似于我们之前的观察，使用外源性给药 炎症介质。此外，活化的白细胞与 血管内皮细胞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 假设用药物阻断循环白细胞的黏附 血管内皮细胞将具有最大的潜力 脓毒症时多器官的微血管损伤。 对这一应用的拟议研究将提供新的信息 白细胞在胃肠道微血管损伤中的作用 在脓毒症期间。因为胃肠道是器官之一 脓毒症期间系统受到不利影响，更好地了解 老年人微循环损伤的病理生理及预防 小肠也应该有利于我们对其他方面的知识 在这种情况下器官功能不全。

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.