Digestive Enzymes and Microvascular Inflammation in Shock

休克时的消化酶和微血管炎症

• 批准号: 8632760
• 负责人: Geert W. Schmid-Schoenbein
• 金额: $ 27.67万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2017-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8632760
• 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; Inflammation; Inflammatory; Injury; Intervention; Intestines; Ischemic Bowel Disease; Lead; 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; Role; Serine Protease; Shock; Small Intestines; Specificity; Symptoms; Testing; Therapeutic; Tight Junctions; Time; Tissues; United States Food and Drug Administration; Vasoconstrictor Agents; Work; artery occlusion; cytotoxic; improved; mortality; multiorgan injury; novel; novel strategies; prevent; public health relevance; receptor; response; therapy design

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)：休克继发多系统器官衰竭是医院患者死亡率最高的原因之一，目前除了减轻症状外，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。在之前的资助期间，我们测试了一种新的假设，即完全激活的、非特异性的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。虽然通常包含在肠腔中作为消化的一部分，但随着粘膜上皮屏障变得可渗透，强大的消化酶泄漏到肠壁中。它们消化肠壁，分解产物进入体循环，导致细胞功能障碍和多系统器官衰竭。这一证据使人们注意到，将消化酶控制在小肠管腔内对预防器官衰竭至关重要。消化酶不会降低正常肠道的粘膜屏障。相反，我们的假设是，在肠缺血期间，粘蛋白屏障的破坏和上皮连接的开放是由肠壁中已存在的一系列不同于消化酶的蛋白酶以及上皮细胞的凋亡途径所介导的。我们将研究目前尚未探索的阻止消化酶逃逸作为休克的主要干预措施的治疗可能性。粘膜屏障的失效还会导致高细胞毒性的游离脂肪酸从摄入的脂肪消化和肠壁消化中移位，而胰腺蛋白酶的移位破坏了作为防御游离脂肪酸的结合蛋白。这些低分子生物分子在休克时的炎症和多器官衰竭中的作用尚不明确。此外，一旦体循环中的蛋白酶活性增加，血管系统中的蛋白质就会降解，包括膜受体。我们推测，受体胞外区的蛋白水解性切割是休克时共病的关键机制，例如，肾上腺素能受体胞外区的蛋白水解性破坏导致对血管加压药维持血压的反应降低，而胞外区紧密连接的切割导致内皮通透性增加。我们将在内脏动脉阻塞性休克模型中研究这些预防休克时急性细胞和器官损伤的中心问题，具体目的如下：1.胰腺消化酶粘膜通透性增加，导致其进入肠壁；2.游离脂肪酸(FFAs)在休克时对肠道和系统器官(如肺)的损害；以及3.休克后多系统器官衰竭，以儿茶酚胺低反应性和酶(蛋白水解性)受体断裂所致的肺衰竭为指标。这项工作将阐明休克时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开辟新的机会。