Relative Contribution of Trypsin and Inflamation in Acute and Chronic Pancreatitis

胰蛋白酶和炎症在急慢性胰腺炎中的相对作用

• 批准号: 9903284
• 负责人: Rajinder K Dawra
• 金额: $ 54.29万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-08-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903284
• 关键词: Acinar Cell; Admission activity; Attenuated; Binding Proteins; Blood Circulation; Caerulein; Cleaved cell; Clinical Trials; Data; Development; Disease; Disintegrins; Endothelium; Enzyme Inhibition; Event; Exposure to; Failure; Functional disorder; Genetic; Grant; Hospitals; Inflammation; Inflammatory; Injury; Intervention; Knock-out; Knockout Mice; Lead; Literature; Lung Inflammation; Mediating; Membrane; Metalloproteases; Modeling; Morbidity - disease rate; Mus; Myelogenous; NF-kappa B; Necrosis; Neutrophilic Infiltrate; Pancreas; Pancreatic Diseases; Pancreatic Injury; Pancreatitis; Pathway interactions; Patients; Peptide Hydrolases; Pharmacology; Play; Positioning Attribute; Process; Proteins; Publishing; Research; Role; Signal Pathway; Stimulus; System; Systemic Inflammatory Response Syndrome; TNF-alpha converting enzyme; Therapeutic; Trypsin; Trypsinogen; United States; acute pancreatitis; antimicrobial; arm; cell injury; chronic pancreatitis; endoplasmic reticulum stress; experience; extracellular; inhibitor/antagonist; knockout animal; lung injury; mortality; neutrophil; novel; novel therapeutics; prophylactic; response

Abstract Pancreatitis, an inflammatory disease of pancreas, leads to more than 300,000 admissions to hospitals in the United States alone. Despite decades of research there is no specific therapy for pancreatitis. While the inflammation during acute pancreatitis is initiated in acinar cells, over disease course the inflammation spills into systemic circulation. Uncontrolled systemic inflammation during acute pancreatitis can lead to Systemic Inflammatory Response Syndrome (SIRS) and multi-organ failure, which is the primary cause of morbidity and mortality. Thus strategies to control inflammation will lead to development of specific therapy for acute pancreatitis. In the current proposal we will evaluate the early intra-acinar events in pancreatitis that lead to activation of signaling pathways that mediate local inflammation, eventually resulting in disease development. In the first aim, we will evaluate the role of ADAMs, specifically ADAM-10/17 in spreading this local inflammation to systemic levels. ADAMs are Zn2+ - dependent proteases that proteolytically cleave a wide variety of membrane-bound proteins. Among these, ADAM-10 and -17 have been implicated in multiple inflammatory disorders but their role has not been evaluated in pancreatitis. Intriguingly, our preliminary data suggest that treatment with ADAM-10/17 inhibitor in a therapeutic setting, i.e. after initiation of injury, leads to decrease in pancreatic and lung injury and inflammation in caerulein model of severe acute pancreatitis. As most of the studies in acute pancreatitis perform prophylactic intervention, which is not clinically significant, the current proposal is focused on evaluating this translationally relevant observation that has the potential of being developed into a therapeutic strategy for pancreatitis. In the next aim, we will study how induction of pancreatitis may result in activation of ER stress in the acinar cells and how this may lead to activation of signaling pathways like AP-1 and NF-kB that are known to be associated with inflammation. We will also evaluate the role of anti-microbial `Neutrophil Extracellular Traps' or NETs, in acinar cell injury in the third aim, which will help us understand the vicious cycle of inflammation and injury in pancreatitis. Since we are in possession of the unique T7 KO mice, we will be in a position to evaluate the role of trypsin in these early intra-acinar events that will eventually help us in understanding the local and systemic inflammation in the context of pancreatic injury.

摘要 胰腺炎是一种胰腺炎性疾病，导致30多万人入院治疗 仅在美国。尽管有几十年的研究，但没有针对胰腺炎的特异性治疗。 虽然急性胰腺炎期间的炎症始于腺泡细胞，但在疾病过程中， 炎症扩散到体循环中。急性期不受控制的全身性炎症 胰腺炎可导致全身炎症反应综合征（SIRS）和多器官衰竭， 这是发病和死亡的主要原因。因此，控制炎症的策略将导致 急性胰腺炎的特异性治疗的发展。在目前的提案中，我们将评估 胰腺炎早期腺泡内事件导致信号通路激活， 炎症，最终导致疾病发展。在第一个目标中，我们将评估 亚当斯，特别是ADAM-10/17在将这种局部炎症扩散到全身水平中的作用。亚当斯是 Zn 2+依赖性蛋白酶，可蛋白水解切割多种膜结合蛋白。 其中，ADAM-10和-17与多种炎症性疾病有关，但它们的作用 尚未在胰腺炎中进行评价。有趣的是，我们的初步数据表明， 在治疗环境中，即在损伤开始后，使用ADAM-10/17抑制剂导致细胞凋亡减少。 急性重症胰腺炎大鼠胰腺和肺损伤及炎症反应的研究大多数与 急性胰腺炎的研究进行了预防性干预，这在临床上不显著， 目前的建议重点是评估这一具有潜在意义的观察结果， 发展成为胰腺炎的治疗策略。在下一个目标中，我们将研究如何 胰腺炎的诱导可能导致腺泡细胞中ER应激的激活， 与AP-1和NF-kB等信号通路的激活有关， 炎症我们还将评估抗微生物的“神经细胞外陷阱”或NET的作用， 腺泡细胞损伤的第三个目标，这将有助于我们了解炎症的恶性循环， 胰腺炎的损伤。由于我们拥有独特的T7 KO小鼠，我们将能够 评估胰蛋白酶在这些早期腺泡内事件中的作用，这将最终帮助我们 了解胰腺损伤背景下的局部和全身炎症。