Digestive Enzymes and Microvascular Inflammation in Shock

休克时的消化酶和微血管炎症

基本信息

批准号：
8037053
负责人：
Geert W. Schmid-Schoenbein
金额：
$ 27.66万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN DIEGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-05-01 至 2013-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8037053
关键词：
Acute Address Allergic Animals Anoxia Antibodies Apoptosis Arteries Attenuated Bacteria Basic Amino Acid Transport Systems Binding Binding Sites Biological Blood Blood Circulation Blood Platelets Brush Border Bypass Cell physiology Cells Clinical Clinical Trials Coin Complement Consensus Cytoplasmic Tail Defect Development Digestion E-Cadherin Endothelial Cells Endothelium Endotoxins Enzymes Epithelial Epithelial Cells Epithelium Event Exposure to Extracellular Domain Failure Family Family suidae Feasibility Studies Functional disorder Generations Greater sac of peritoneum Health Hemorrhagic Shock Hepatic Hour Human Hypovolemics Hypoxia Immunosuppression In Vitro Individual Inflammation Inflammation Mediators Inflammatory Injury Insulin Receptor Insulin Resistance Intervention Intestines Ischemia Knowledge Lead Leukocytes Light Lipase Lipids Liver Location Lung Lymphatic Measurement Measures Mediator of activation protein Medical Membrane Mesentery Metabolic Microcirculation Molecular Organ Organ failure Pancreas Pancreatic enzyme Pathogenesis Pathologic Pathway interactions Peptide Hydrolases Perfusion Peripheral Peritoneal Fluid Peritoneum Permeability Phase Physiological Plasma Play Preparation Prevention Process Production Protease Inhibitor Proteins Rattus Reaction Research Role Serine Protease Serous Membrane Shock Source Staging Submucosa Symptoms Techniques Testing Tight Junctions Time Tissues Toxic Shock Syndrome Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factor Receptor-2 Venous Weight Gain Work artery occlusion base cadherin 5 cell injury cytokine cytotoxic effective intervention extracellular improved in vivo inhibitor/antagonist interstitial intestinal epithelium junctional adhesion molecule mortality neurogenic shock novel strategies occludin pre-clinical preclinical study prevent receptor reconstitution research study septic therapy development

项目摘要

DESCRIPTION (provided by applicant): Physiological shock and multi-organ failure is one of the most important medical problems with high mortality. A powerful inflammatory cascade accompanies shock, but there is no consensus for the trigger mechanisms of the inflammation. It is our long-term objective to identify the origin of the inflammation in shock and develop new interventions to minimize the inflammation and multi-organ failure. We recently developed a new line of research that has served to identify pancreatic digestive enzymes in the intestine as key players in shock. This family of enzymes is usually restricted to the lumen of the intestine as part of normal digestion. The digestive enzymes are present in comparatively high concentrations as part of normal digestion, capable to degrade most biological molecules and entire tissues within hours. Under normal circumstances, the digestive enzymes are retained within the lumen of the intestine by the mucosal barrier. But under conditions of shock, the same digestive enzymes are transported from the lumen into the wall of the intestine. Once inside the wall, they initiate an auto-digestion process with release of pancreatic enzymes as well as inflammatory digestive products into the central circulation where they cause cell injury and multi-organ failure. We obtained preliminary evidence to indicate that blockade of the digestive enzymes in the lumen of the intestine dramatically reduces the production of inflammatory mediators and significantly improves survival after severe forms of shock. It is our hypothesis that in hemorrhagic shock the protective barrier normally provided by the brush border epithelium is compromised and allows access of preexisting digestive enzymes into interstitial tissue in the wall of the intestine. The digestive enzymes are carried through multiple pathways into the central circulation where they cause microvascular inflammation and major cell dysfunctions by enzymatic cleavage of membrane receptors, e.g. cleavage of the extracellular domain of tight junction proteins and irreversible elevation of epithelial and endothelial permeability or cleavage of the extracellular binding site of the insulin receptor and insulin resistance. Blockade of the pancreatic enzymes and temporary prevention of digestion in the lumen of the intestine serves to prevent inflammation and reduces mortality due to multi-organ failure. Thus we propose to investigate the following three important Specific Aims: 1. Determine in hemorrhagic shock the activity and transport of the pancreatic digestive enzymes from the lumen of the intestine along multiple pathways into the peripheral microcirculation and the level of the associated microvascular inflammatory reaction. 2. Determine by enzyme blockade in the lumen of the intestine the role of pancreatic digestive enzymes in generation of inflammatory and cytotoxic mediators and in long-term survival after hemorrhagic shock. 3. Measure the level of extracellular receptor cleavage by proteases associated with failure of tight junctions and loss of key cell functions during the early stage of shock. These studies will determine the mechanisms for the origin of the powerful cell and organ injury mechanisms in shock. We will test a new form of intervention against the high mortality in shock that may have clinical utility.

描述（由申请人提供）：生理休克和多器官衰竭是最重要的医学问题之一，死亡率很高。休克伴随着强大的炎症级联反应，但对于炎症的触发机制尚未达成共识。我们的长期目标是确定休克炎症的根源并开发新的干预措施以尽量减少炎症和多器官衰竭。我们最近开展了一系列新的研究，旨在确定肠道中的胰腺消化酶是休克的关键因素。作为正常消化的一部分，该酶家族通常仅限于肠腔。作为正常消化的一部分，消化酶以相对较高的浓度存在，能够在数小时内降解大多数生物分子和整个组织。正常情况下，消化酶通过粘膜屏障保留在肠腔内。但在休克的情况下，相同的消化酶会从管腔转运到肠壁。一旦进入壁内，它们就会启动自动消化过程，将胰酶和炎症消化产物释放到中央循环中，导致细胞损伤和多器官衰竭。我们获得的初步证据表明，阻断肠腔中的消化酶可以显着减少炎症介质的产生，并显着提高严重休克后的生存率。我们的假设是，在失血性休克中，通常由刷状缘上皮提供的保护屏障受到损害，并允许预先存在的消化酶进入肠壁的间质组织。消化酶通过多种途径进入中央循环，在那里它们通过膜受体的酶裂解引起微血管炎症和主要细胞功能障碍。紧密连接蛋白胞外结构域的裂解以及上皮和内皮渗透性的不可逆升高或胰岛素受体胞外结合位点的裂解和胰岛素抵抗。阻断胰酶和暂时阻止肠腔内的消化可以预防炎症并降低多器官衰竭引起的死亡率。因此，我们建议研究以下三个重要的具体目标： 1. 确定失血性休克中胰腺消化酶从肠腔沿多种途径进入外周微循环的活性和运输以及相关微血管炎症反应的水平。 2. 通过肠腔内的酶阻滞来确定胰腺消化酶在炎症和细胞毒性介质的产生以及失血性休克后的长期存活中的作用。 3. 测量休克早期阶段与紧密连接失败和关键细胞功能丧失相关的蛋白酶对细胞外受体的裂解水平。这些研究将确定休克中强大的细胞和器官损伤机制的起源机制。我们将测试一种可能具有临床实用性的针对休克高死亡率的新干预措施。