Role of Intra-Pancreatic Trypsinogen Activation in Alcoholic Pancreatitis

摘要胰腺炎是胰腺的一种炎症性疾病，发病率和死亡率高，最常与酒精滥用有关。然而，酒精性胰腺炎的发病机制尚不清楚。据信，酒精使胰腺对遗传或环境因素敏感。一个挑战仍然是确定致敏因素，确定它们对损伤的贡献，并了解乙醇致敏效应的机制。因此，毫无疑问，需要更好地了解酒精性胰腺炎的病理生理机制，以开发针对该疾病的靶向治疗。现有的非酒精性胰腺炎模型研究表明胰蛋白酶原激活在胰腺炎发病机制中的作用。已知酒精暴露可增强腺泡细胞中胰蛋白酶原的激活。人类酗酒者的胰液中发现胰蛋白酶原水平增高。这些变化被认为使腺泡细胞更容易受伤。这些发现提示胰腺胰蛋白酶原激活可能是酒精性胰腺炎发病机制的中心事件，尽管没有直接的实验证据证明这一点。乙醇暴露还有其他一些有害影响，如改变NFkB激活和扰乱内质网应激反应，这些都有可能导致胰腺损伤。最近，我们培育了缺乏胰蛋白酶原7（小鼠阳离子胰蛋白酶原）的敲除小鼠。这些小鼠未表现出胰蛋白酶原的病理性活化。组织蛋白酶B的活性是胰蛋白酶原在腺泡内激活所必需的，组织蛋白酶B基因缺失的小鼠也缺乏病理性胰蛋白酶原激活。我们对这两种小鼠品系的接触使我们处于一个独特的位置，以确定胰蛋白酶原激活在酒精性胰腺炎发病机制中的作用。在没有胰蛋白酶原激活的情况下，我们也将能够了解是否其他乙醇暴露诱导的有害事件在疾病的发病机制中有任何作用。在这项拨款申请中，我们将验证这样一种假设，即胰蛋白酶原的腺泡内激活是酒精性胰腺炎的关键早期事件，导致腺泡细胞损伤和炎症途径的激活，从而导致急性胰腺炎，当这些事件延长时，这些事件会导致酒精性胰腺炎的纤维化和慢性炎症反应。这些研究的完成，在明确胰蛋白酶原激活在酒精滥用诱导致敏中的作用的同时，将为未来的研究奠定基础，重点是了解其他乙醇诱导的胰腺事件的作用，并寻找酒精性胰腺炎的潜在治疗靶点。

DESCRIPTION (provided by applicant): Role of intra-pancreatic trypsinogen activation in alcoholic pancreatitis ABSTRACT Pancreatitis is an inflammatory disease of the pancreas associated with significant morbidity and mortality and is most commonly associated with alcohol abuse. However, the mechanism of alcoholic pancreatitis is not clear. It is believed that alcohol sensitizes the pancreas to genetic or environmental predisposing factors. A challenge remains to identify sensitization factors, to define their contribution to the injury and to understand the mechanisms of ethanol sensitizing effects. There is therefore an inarguable need to better understand the patho-physiological mechanism of alcoholic pancreatitis to develop a targeted therapy for the disease. Existing studies in non-alcoholic models of pancreatitis suggest a role for trypsinogen activation within the pancreas in the pathogenesis of the disease. Alcohol exposure is known to enhance activation of trypsinogen in acinar cells. Pancreatic juice of human alcoholics was found to have increased levels of trypsinogens. These changes are thought to make acinar cells more prone to injury. These findings suggest that trypsinogen activation in the pancreas might be the central event in the pathogenesis of alcoholic pancreatitis, although there is no direct experimental evidence to prove this. Ethanol exposure has several other deleterious effects like altered NFkB activation and perturbed endoplasmic reticulum stress response, which have the potential to cause pancreatic damage. Recently, we have developed knockout mice lacking trypsinogen 7, the mouse cationic trypsinogen. These mice do not show pathological activation of trypsinogen. Cathepsin B activity is required for intra-acinar activation of trypsinogen and the mice with cathepsin B gene deletion also lack pathological trypsinogen activation. Our access to these two strains of mice places us in a unique position to define the role of trypsinogen activation in the pathogenesis of alcoholic pancreatitis. In the absence of trypsinogen activation, we will also be able to understand if other ethanol exposure-induced deleterious events have any role in pathogenesis of the disease. In this grant proposal, we will be testing the hypothesis that intra-acinar activation of trypsinogen is the critical early event in alcoholic pancreatitis leading to acinar cll injury and activation of inflammatory pathways which result in acute pancreatitis and when prolonged, these events leads to fibrosis and chronic inflammatory response of alcoholic pancreatitis. Completion of these studies, while clearly defining the role of trypsinogen activatio in alcohol abuse induced sensitization, will lay the foundation for future investigations focused on understanding the role of other ethanol induced events in the pancreas and the searching for potential therapeutic targets in alcoholic pancreatitis.