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.

有人假设，在屏障功能的紊乱， 肠道使重症患者易于发生菌血症， 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，如51 Cr-EDTA。 肠上皮细胞对 亲水性溶质的功能状态取决于 细胞间紧密连接（闭锁小带; ZO）。 最近的数据表明 ZO在解剖学和功能上与细胞骨架相连。 其他结果表明，组织的完整性， 细胞骨架依赖于维持足够的细胞内水平 的ATP。 由于细胞缺氧和氧化应激都可以干扰 ATP合成，我们假设脂多糖（LPS）诱导的 粘膜通透性过高是由肠上皮细胞中的ATP耗竭引起的。 因此，我们将研究缺血和氧化诱导的粘膜ATP 消耗作为内毒素对肠道的不利影响的机制 上皮通透性 拟议的研究将使用猪 内毒素中毒模型，令人满意地再现了许多血流动力学 在复苏的病人中感染性休克的表现。 粘膜 将通过测量血浆-管腔清除率来定量渗透性 51Cr-EDTA 将使用多导丝测量粘液氧合 允许监测O2的Clark型表面电极阵列 组织的多个微观半球（半径约20 μ M）中的张力。 使用这些方法，我们将评估LPS对细胞的时间依赖性影响。 粘膜氧合、ATP含量和渗透性。 此外，我们会 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： 维持正常的上皮氧合，或者通过泵灌注 用含氧血液或灌注肠腔的血管供应 用含氧缓冲液清洗肠道 此外，我们还将研究 通过评估别嘌呤醇（一种黄嘌呤氧化酶） 抑制剂）或氧自由基清除剂， 内毒素动物体内ATP含量。 最后，我们将评估 粘膜缺氧或氧化应激对粘膜ATP含量和通透性的影响 正常的猪。 这些研究应该提供新的见解， 脓毒症中粘膜通透性过高的机制， 内毒素中毒