Hemorrhagic Shock and Pancreatic Enzyme Products

失血性休克和胰酶产品

• 批准号: 6849804
• 负责人: David B. Hoyt
• 金额: $ 36.6万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2008-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6849804
• 关键词: cardiovascular disorder chemotherapy; cardiovascular function; dosage; drug delivery systems; drug screening /evaluation; enzyme inhibitors; hemorrhagic shock; inflammation; intestines; ischemia; multiple organ failure; pancreas enzyme; protease inhibitor; swine

DESCRIPTION (provided by applicant): Hemorrhagic shock is accompanied by a strong inflammatory reaction, the origin of which has been hypothesized in the past to be associated with specific mediators such as endotoxin, oxygen free radicals, cytokines and platelet activating factor. No conclusive evidence has been advanced that may lead to clinical utility. Instead, we have recently obtained evidence indicating that the powerful digestive enzymes, synthesized in the pancreas as part of normal digestion, may play a central role in shock and multiorgan failure. These powerful enzymes have the ability to digest almost all biological tissues. Self-digestion is prevented by compartmentalization of the fully activated enzymes in the lumen of the intestine by the mucosal epithelial barrier. In hemorrhagic shock, the mucosal barrier becomes permeable to pancreatic enzymes. The digestive enzymes enter into the wall of the intestine and initiate self-digestion of autologous submucosal extracellular matrix proteins and tissue cells, a process which leads to the production of inflammatory mediators. As an early line of defense, we hypothesize that inhibition of pancreatic enzymes in the lumen of the intestine serves to attenuate the formation of inflammatory mediators in hemorrhagic shock and consequently cell and tissue injury as well as multiorgan failure. Accordingly, we propose the following three specific aims in a porcine model of severe hemorrhagic shock: I. To examine different levels of pressure reductions and ischemic periods and their impact on the effectiveness of pancreatic enzyme inhibition to reduce the effects of inflammatory factors and improve cardiovascular function in this model; II. To examine different pancreatic enzyme inhibitors and determine optimal dosages for these enzyme inhibitors and method of delivery; and III. To evaluate the impact of intra-luminal protease inhibition in the intestine on mortality and end organ failure over 7 days after severe hemorrhagic shock. Our preliminary results indicate that blockade of digestive enzymes (serine proteases, lipases) in the lumen of the intestine provides a highly significant protection against formation of inflammatory mediators and early symptoms of multiorgan failure. The results of this research provide not only an approach to examine the different enzymatic and inflammatory processes in hemorrhagic shock but also to directly serve as the basis for possible intervention in patients.

描述（由申请人提供）： 出血性休克伴随着强烈的炎症反应，过去假设其起源与特定介质如内毒素、氧自由基、细胞因子和血小板活化因子相关。尚未提出可能导致临床效用的结论性证据。相反，我们最近获得的证据表明，作为正常消化的一部分，在胰腺中合成的强大的消化酶可能在休克和多器官衰竭中发挥核心作用。这些强大的酶具有消化几乎所有生物组织的能力。通过粘膜上皮屏障将肠腔中完全活化的酶区室化来防止自我消化。在出血性休克中，粘膜屏障变得对胰酶可渗透。消化酶进入肠壁并启动自体粘膜下细胞外基质蛋白和组织细胞的自我消化，这是导致炎症介质产生的过程。作为早期的防线，我们假设，抑制肠腔中的胰腺酶可以减弱出血性休克中炎症介质的形成，从而减轻细胞和组织损伤以及多器官衰竭。因此，我们提出了以下三个具体目标，在猪严重失血性休克模型：I。 在该模型中，检查不同水平的减压和缺血期及其对胰腺酶抑制的有效性的影响，以减少炎症因子的影响并改善心血管功能; II.检查不同的胰腺酶抑制剂并确定这些酶抑制剂的最佳剂量和递送方法;和III.评价肠腔内蛋白酶抑制对重度失血性休克后7天内死亡率和终末器官衰竭的影响。我们的初步研究结果表明，肠腔中消化酶（丝氨酸蛋白酶，脂肪酶）的阻断提供了非常显着的保护，防止炎症介质的形成和多器官衰竭的早期症状。这项研究的结果不仅提供了一种方法来检查不同的酶和炎症过程中失血性休克，但也直接作为可能的干预患者的基础。