Microvascular Injury and Pancreatic Enzyme Products

描述（由申请人提供）：其中一个重要的未解决的问题， 生理冲击是了解导致形成的机制， 炎症级联反应休克伴随着细胞活化， 微循环、白细胞浸润、细胞功能障碍、细胞凋亡和器官 失败我们最近获得的证据表明，胰腺酶作为一种 是产生体液炎性介质的有力来源， 肠缺血缺血性脑血管病的胰蛋白酶阻断 肠道导致高水平的保护，防止炎症， 多器官衰竭我们的研究结果表明胰腺癌在 丝氨酸蛋白酶根据这一证据，我们假设， 肠道中的胰腺消化酶可以通过刷子逃逸 边界细胞屏障缺血，其后产生体液炎性 通过消化细胞外基质蛋白和其他细胞因子 件.我们的具体目标是：（1）确定特定的胰腺酶 有助于体液微血管激活剂产生的活动， 缺血性肠腔内酶阻断导致失血性休克， 通过将纯化的胰酶引入小的 （2）检测胰腺酶在组织中的定位 在肠缺血前后，并确定产生 在小的间质空间中的炎性介质产生 肠;（3）检查炎症启动的分子机制 在外周器官中，胰腺酶产生激活物后， 肠;和（4）纯化和表征选定的炎症介质 由胰腺匀浆中的胰酶产生，作为一种普遍存在的 炎症介质的来源和纯化的细胞外基质的来源 基质蛋白（包括纤连蛋白、玻连蛋白和胶原蛋白I、III和III）， IV）与丝氨酸蛋白酶。我们将研究，使用最先进的数字 体内显微镜检查，胰腺酶的转运和作用 休克大鼠炎症介质的生化鉴定 模型促进炎症介质的生化鉴定 通过从收获的大鼠获得大量起始材料， 猪胰腺组织。了解炎症的触发机制， 休克将导致人类新治疗方式。

DESCRIPTION (provided by applicant): One of the important unresolved issues in physiological shock is understanding the mechanism leading to formation of an inflammatory cascade. Shock is accompanied by cell activation in the microcirculation, leukocyte infiltration, cell dysfunction, apoptosis and organ failure. We recently obtained evidence that pancreatic enzymes serve as a powerful source for generation of humoral inflammatory mediators in the ischemic intestine. Blockade of pancreatic enzymes in the lumen of the ischemic intestine leads to high levels of protection against inflammation and multi-organ failure. Our results point to an important role for pancreatic serine proteinases. In accordance with this evidence we hypothesize that pancreatic digestive enzymes in the intestine can escape across the brush border cell barrier during ischemia and thereafter produce humoral inflammatory mediators by digestion of extracellular matrix proteins and other cellular components. Our Specific Aims are (1) to identify specific pancreatic enzyme activities which contribute to humoral microvascular activator production in hemorrhagic shock by enzyme blockade in the lumen of the ischemic intestine and by introduction of purified pancreatic enzymes into the lumen of the small intestine; (2) to examine the pancreatic enzyme localization in the tissue before and after intestinal ischemia and determine the production of inflammatory mediator production in the interstitial space of the small intestine; (3) to examine molecular mechanisms for initiation of inflammation in a peripheral organ after activator production by pancreatic enzymes in the intestine; and (4) to purify and characterize selected inflammatory mediators produced by pancreatic enzymes from homogenates of pancreas as an ubiquitous source of inflammatory mediators and from digests of purified extracellular matrix proteins (including fibronectin, vitronectin, and collagen I, III and IV) with serine proteinases. We will study, using state of the art digital in-vivo microscopy, transport and action of pancreatic enzymes in combination with biochemical identification of inflammatory mediators in the rat shock model. Biochemical identification of the inflammatory mediators is facilitated by availability of large quantities of starting material from harvested rat and pig pancreatic tissue. Understanding the trigger mechanisms for inflammation in shock will lead to new treatment modalities in man.