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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：
9187459
负责人：
Geert W. Schmid-Schoenbein
金额：
$ 27.26万
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 2018-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9187459
关键词：
Acute Adrenergic Receptor Apoptosis Binding Proteins Blood Circulation Blood Pressure Catecholamines Cell membrane Cells Cessation of life Cleaved cell Clinical Comorbidity Containment Critical Illness Digestion Edema Enzymes Epithelial Epithelial Cell Junction Epithelial Cells Epithelium Exhibits Extracellular Matrix Degradation Failure Fatty acid glycerol esters Functional disorder Funding Germ Cells Goals Hospitals Impairment Inflammation Inflammatory Injury Intervention Intestines Ischemic Bowel Disease Lipase Lung Matrix Metalloproteinases Measures Mediating Mediator of activation protein Membrane Modeling Molecular Molecular Weight Morbidity - disease rate Mucins Necrosis Nonesterified Fatty Acids Organ Organ failure Pancreas Patients Pattern Peptide Hydrolases Permeability Pharmaceutical Preparations Play Prevention Prevention strategy Property Proteins Reaction Resistance Respiratory Failure Role Serine Protease Shock Small Intestines Specificity Testing Therapeutic Tight Junctions Time Tissues Treatment Failure United States Food and Drug Administration Vasoconstrictor Agents Work artery occlusion cytotoxic improved mortality novel novel strategies prevent public health relevance receptor reduce symptoms response therapy design

项目摘要

DESCRIPTION (provided by applicant): Shock followed by multisystem organ failure is associated with one of the highest mortalities in hospital patients and there is currently no treatment other than alleviation of symptoms. Our objective is to determine molecular mechanisms for initial cell and organ damage and open new possibilities for intervention. In the previous funding period we tested a new hypothesis that the fully activated, non-specific pancreatic digestive enzymes play a central role in cell and organ dysfunction and death. While normally contained in the lumen of the intestine as part of digestion, the powerful digestive enzymes leak into the wall of the intestine as the mucosal epithelial barrier becomes permeable. They digest the intestinal wall and their breakdown products escape into the systemic circulation where they cause cell dysfunction and multisystem organ failure. This evidence has brought into focus that containment of the digestive enzymes inside the lumen of the small intestine is of paramount importance to prevent organ failure. Digestive enzymes do not degrade the mucosal barrier in a normal intestine. Instead, our hypothesis is that during intestinal ischemia, breakdown of the mucin barrier and opening of epithelial junctions is mediated by a set of proteases already present in the intestinal wall and different from digestive enzymes as well as by an apoptosis pathway in the epithelium. We will investigate the currently unexplored, therapeutic possibility of blocking the escape of digestive enzymes as a primary intervention in shock. Failure of the mucosal barrier also results in the translocation of the highly cytotoxic unbound free fatty acids from digestion of ingested fats and from digestion of the intestinal wall while translocation of pancreatic proteases destroys the binding proteins that act as a defense against free fatty acids. The contribution of these low molecular weight biomolecules to inflammation and multiorgan failure in shock is undefined. Furthermore, once protease activity in the systemic circulation increases, proteins in the vasculature are subject to degradation, including membrane receptors. We hypothesize that proteolytic cleavage of receptor ectodomains is a key mechanism for comorbidities in shock, e.g. proteolytic destruction of the ectodomain of adrenergic receptors leads to a reduced response to vasopressor drugs to maintain blood pressure, and ectodomain tight junction cleavage leads to elevated endothelial permeability. We will investigate these central issues for prevention of acute cell and organ damage in shock in a model of splanchnic arterial occlusion shock by the following Specific Aims: Determine the mechanisms for 1. Elevated mucosal permeability to pancreatic digestive enzymes that results in their entry into the wall of the intestine in shock; 2. damage to the intestine and systemic organs (e.g. lungs) during shock by unbound free fatty acids (FFAs); and 3. multisystem organ failure in response to shock, as measured by catecholamine hypo-responsiveness and pulmonary failure due to enzymatic (proteolytic) receptor cleavage. This work will elucidate mechanisms for acute tissue injury and consequent organ dysfunction in shock and open new opportunities to intervene with the morbidity and high mortality of critically ill patients.

描述（由申请人提供）：休克后多系统器官衰竭是住院患者死亡率最高的疾病之一，目前除缓解症状外没有其他治疗方法。我们的目标是确定初始细胞和器官损伤的分子机制，并为干预开辟新的可能性。在上一个资助期间，我们测试了一个新的假设，即完全激活的非特异性胰腺消化酶在细胞和器官功能障碍和死亡中发挥核心作用。虽然通常作为消化的一部分包含在肠腔中，但随着粘膜上皮屏障变得可渗透，强大的消化酶会泄漏到肠壁中。它们消化肠壁，其分解产物逃逸到体循环中，在那里它们引起细胞功能障碍和多系统器官衰竭。这一证据使人们注意到，将消化酶限制在小肠腔内对防止器官衰竭至关重要。消化酶不降解正常肠中的粘膜屏障。相反，我们的假设是，在肠缺血期间，粘液屏障的破坏和上皮连接的开放是由一组已经存在于肠壁中的蛋白酶介导的，并且不同于消化酶以及上皮细胞凋亡途径。我们将研究目前尚未探索的，治疗的可能性，阻断逃逸的消化酶作为一个主要的干预休克。粘膜屏障的失效还导致来自消化摄入的脂肪和来自消化肠壁的高度细胞毒性的未结合的游离脂肪酸的易位，而胰腺蛋白酶的易位破坏了作为抵抗游离脂肪酸的防御的结合蛋白。这些低分子量生物分子对休克中炎症和多器官衰竭的作用尚不清楚。此外，一旦体循环中的蛋白酶活性增加，脉管系统中的蛋白质（包括膜受体）就会发生降解。我们假设受体胞外域的蛋白水解裂解是休克合并症的关键机制，例如肾上腺素能受体胞外域的蛋白水解破坏导致对血管加压药维持血压的反应降低，胞外域紧密连接裂解导致内皮通透性升高。我们将研究这些中心问题，以预防急性细胞和器官损伤的休克模型内脏动脉闭塞休克的具体目标如下：确定机制1。胰腺消化酶的粘膜渗透性升高，导致其在休克时进入肠壁; 2.休克期间未结合的游离脂肪酸（FFA）对肠和全身器官（例如肺）的损伤;和3.休克后多系统器官衰竭，如通过儿茶酚胺低反应性和酶（蛋白水解）受体裂解导致的肺衰竭所测量。这项工作将阐明休克中急性组织损伤和随后的器官功能障碍的机制，并为干预危重患者的发病率和高死亡率提供新的机会。

项目成果

期刊论文数量（16）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Proteolytic Activity Attenuates the Response of Endothelial Cells to Fluid Shear Stress.

DOI：
10.1007/s12195-011-0207-6
发表时间：
2012-03
期刊：
CELLULAR AND MOLECULAR BIOENGINEERING
影响因子：
2.8
作者：
Altshuler, Angelina E.;Morgan, Mary J.;Chien, Shu;Schmid-Schoenbein, Geert W.
通讯作者：
Schmid-Schoenbein, Geert W.

Effect of digestion and storage of human milk on free fatty acid concentration and cytotoxicity.

母乳消化和储存对游离脂肪酸浓度和细胞毒性的影响。

DOI：
10.1097/mpg.0000000000000441
发表时间：
2014
期刊：
Journal of pediatric gastroenterology and nutrition
影响因子：
2.9
作者：
Penn,AlexanderH;Altshuler,AngelinaE;Small,JamesW;Taylor,SharonF;Dobkins,KarenR;Schmid-Schönbein,GeertW
通讯作者：
Schmid-Schönbein,GeertW

Transmural intestinal wall permeability in severe ischemia after enteral protease inhibition.