Hemorrhagic Shock and Pancreatic Enzyme Products

失血性休克和胰酶产品

• 批准号: 7188562
• 负责人: David B. Hoyt
• 金额: $ 30.24万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 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 2010-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7188562
• 关键词: Apoptosis; Attenuated; Autologous; Biochemical; Biological; Blood Circulation; Blood Vessels; Cardiovascular Physiology; Cell Adhesion Molecules; Cells; Cessation of life; Class; Clinical; Coagulation Process; Compatible; Complement; Complex Mixtures; Condition; Digestion; Disseminated Intravascular Coagulation; Distant; Doctor of Medicine; Early treatment; Effectiveness; Elements; Endopeptidases; Endotoxins; Enzyme Inhibition; Enzyme Inhibitor Drugs; Enzyme Inhibitors; Enzymes; Epithelial; Extracellular Matrix Proteins; Failure; Family suidae; Free Radicals; Functional disorder; Future; Generations; Hemorrhagic Shock; Hour; In Vitro; Inflammation; Inflammatory; Injury; Intervention; Intestines; Ischemic Bowel Disease; Laboratories; Lead; Leukocytes; Light; Lipase; Lipids; Lymph; Lymphatic; Mediating; Mediator of activation protein; Membrane; Methods; Microcirculation; Modeling; Numbers; Organ; Organ failure; Outcome; Pancreas; Pancreatic enzyme; Pathology; Pathway interactions; Patients; Peptide Hydrolases; Perfusion; Plasma; Platelet Activating Factor; Play; Principal Investigator; Procedures; Process; Production; Protease Inhibitor; Range; Rattus; Reaction; Research; Research Personnel; Resuscitation; Risk; Role; Series; Serine; Serine Protease; Shock; Source; Study Section; Sus scrofa; Symptoms; Techniques; Testing; Tissues; Title; Triage; Venous; base; cell type; cytokine; day; design; dosage; enzyme activity; free radical oxygen; improved; in vivo; inhibitor/antagonist; insight; interstitial; mortality; non-genomic; novel; pre-clinical; pressure; prevent; research study; response; therapy design

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)： 失血性休克伴随着强烈的炎症反应，过去认为其起源与内毒素、氧自由基、细胞因子和血小板激活因子等特定介质有关。目前还没有确凿的证据表明这可能会导致临床实用。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。这些强大的酶能够消化几乎所有的生物组织。通过粘膜上皮屏障将肠腔中的完全激活的酶隔开，从而阻止了自我消化。失血性休克时，粘膜屏障对胰酶具有通透性。消化酶进入肠壁，启动自体粘膜下细胞外基质蛋白和组织细胞的自我消化，这一过程导致炎症介质的产生。作为一条早期的防线，我们假设抑制肠腔中的胰酶有助于减轻失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，我们在猪严重失血性休克模型中提出了以下三个具体目标：一、检测不同程度的降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，改善心血管功能；二、检测不同的胰酶抑制剂，并确定这些酶抑制剂的最佳剂量和给药方法；三、评估严重失血性休克后7天内肠腔内蛋白酶抑制对死亡率和终末器官衰竭的影响。我们的初步结果表明，阻断肠腔中的消化酶(丝氨酸蛋白酶、脂肪酶)对炎症介质的形成和多器官衰竭的早期症状具有非常显著的保护作用。这项研究的结果不仅为研究失血性休克不同的酶和炎症过程提供了一种方法，而且还直接作为患者可能进行干预的基础。

项目成果

Breakdown of mucin as barrier to digestive enzymes in the ischemic rat small intestine.

• DOI: 10.1371/journal.pone.0040087
• 发表时间: 2012
• 期刊: PloS one
• 影响因子: 3.7
• 作者: Chang M;Alsaigh T;Kistler EB;Schmid-Schönbein GW
• 通讯作者: Schmid-Schönbein GW