INTESTINAL PERFUSION AND PERMEABILITY IN SEPSIS

脓毒症的肠道灌注和渗透性

• 批准号: 2178851
• 负责人: Mitchell P. Fink
• 金额: $ 21.36万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1996-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2178851
• 关键词: adenylate kinase; allopurinol; antioxidants; bacterial disease; biopsy; blood toxicology; cytoskeleton; disease /disorder model; endotoxins; free radical scavengers; gastrointestinal circulation; gastrointestinal epithelium; gastrointestinal toxin absorption; intercellular connection; intestinal mucosa; ischemia; lipopolysaccharides; membrane permeability; microelectrodes; myeloperoxidase; oxygen tension; radiotracer; septic shock; swine

It has been hypothesized that derangements in the barrier function of the gut predispose critically ill patients to the development of bacteremia, fungemia, and endotoxicosis. The integrity of the epithelial barrier can be assessed by measuring its permeability to certain water-soluble compounds, such as 51Cr-EDTA. The permeability of the gut epithelium to hydrophilic solutes is determined by the functional status of the intercellular tight junctions (zonula occludens; ZO). Recent data suggest that the ZO is anatomically and functionally linked to the cytoskeleton. Other results indicate that the organizational integrity of the cytoskeleton depends upon the maintenance of adequate intracellular levels of ATP. Since both cellular hypoxia and oxidant stress can interfere with ATP synthesis, we have hypothesized that lipopolysaccharide (LPS)-induced mucosal hyperpermeability is caused by ATP depletion in enterocytes. Accordingly, we will investigate ischemia- and oxidant-induced mucosal ATP depletion as mechanisms for the adverse effect of endotoxin on gut epithelial permeability. The proposed studies will utilize a porcine endotoxicosis model that satisfactorily reproduces many of the hemodynamic manifestations of septic shock in resuscitated patients. Mucosal permeability will be quantitated by measuring the plasma-to-lumen clearance of 51Cr-EDTA. Mucosal oxygenation will be measured using a multiwire Clark-type surface electrode array that permits the monitoring of 02 tensions in multiple microscopic hemispheres (radius~20 uM) of tissue. Using these methods, we will assess the time-dependent effects of LPS on mucosal oxygenation, ATP content, and permeability. In addition, we will determine whether LPS-induced mucosal hyperpermeability can be prevented by maintaining normal epithelial oxygenation, either by pump-perfusing the vascular supply of the gut with oxygenated blood or perfusing the lumen of the gut with oxygenated buffer. Also, we will investigate the role of oxidants by assessing the effects of allopurinol (a xanthine oxidase inhibitor) or oxygen free-radical scavengers of mucosal permeability and ATP content in endotoxic animals. Finally, we will assess the affects of mucosal hypoxia or oxidant stress on mucosal ATP content and permeability in normal pigs. These studies should provide new insights into the mechanisms responsible for mucosal hyperpermeability in sepsis and endotoxicosis.

据推测，屏障功能紊乱 肠道易使危重患者发生菌血症， 真菌血症和内毒素中毒。 上皮屏障的完整性可以 通过测量其对某些水溶性物质的渗透性来评估 化合物，例如 51Cr-EDTA。 肠道上皮细胞的通透性 亲水性溶质由亲水性溶质的功能状态决定 细胞间紧密连接（闭合小带；ZO）。 最新数据表明 ZO 在解剖学和功能上与细胞骨架相关。 其他结果表明，组织完整性 细胞骨架取决于维持足够的细胞内水平 ATP。 由于细胞缺氧和氧化应激都会干扰 ATP 合成，我们假设脂多糖 (LPS) 诱导 粘膜通透性过高是由肠上皮细胞中 ATP 耗竭引起的。 因此，我们将研究缺血和氧化诱导的粘膜 ATP 耗竭是内毒素对肠道不利影响的机制 上皮通透性。 拟议的研究将利用猪 令人满意地再现许多血流动力学的内毒素中毒模型 复苏患者感染性休克的表现。 粘膜 通过测量血浆与管腔的清除率来定量渗透性 51Cr-EDTA。 将使用多线测量粘膜氧合 克拉克型表面电极阵列，可监测 02 组织多个微观半球（半径~20 uM）的张力。 使用这些方法，我们将评估 LPS 对时间的影响 粘膜氧合、ATP 含量和渗透性。 此外，我们将 确定是否可以通过以下方法预防 LPS 诱导的粘膜通透性过高 通过泵灌注维持正常的上皮氧合 肠道血管供应含氧血液或灌注肠腔 具有含氧缓冲液的肠道。 此外，我们还将研究以下角色的作用： 通过评估别嘌呤醇（一种黄嘌呤氧化酶）的作用来识别氧化剂 抑制剂）或粘膜通透性的氧自由基清除剂和 内毒素动物中的 ATP 含量。 最后，我们将评估影响 粘膜缺氧或氧化应激对粘膜 ATP 含量和通透性的影响 在正常猪中。 这些研究应该为以下问题提供新的见解： 败血症和粘膜通透性过高的机制 内毒素中毒。