ROLE FOR VIRAL INFECTION IN ALCOHOLIC PANCREATITIS

描述(由申请人提供)： 人类的胰腺炎病例中有很大一部分与饮酒有关，但只有少数酗酒的人会患上胰腺炎。这些观察结果支持了酒精或酒精代谢以外的因素参与酒精性胰腺炎发展的论点。在这项探索性/发展性拨款申请中提出的研究将调查的假设是，急性和慢性酒精性胰腺炎发生的一个辅助因素是感染了一种对胰腺有趋向性的病毒。这种病毒感染被认为是胰腺损伤的始作俑者，这种损伤在通过与酒精相关的胰腺敏化而滥用酒精的人中更为严重。这些研究将使用C57BL/6和Balb/c小鼠建立的酒精消费模型，这些小鼠在液体饮食或饮用水中提供乙醇(Etoh)。具体地说，提供乙醇的小鼠和对照组小鼠(即配对喂养和喂食的小鼠)将感染B组柯萨奇病毒，定型3(CVB3)，并将评估胰腺损伤和纤维化。这些假设将通过三个特定的目的来解决：1)建立模型系统来表征Etoh和CVB3感染对胰腺的影响；2)确定Etoh的摄入对病毒感染期间促炎细胞因子的产生的影响；3)利用饮用水中的Etoh模型系统来确定慢性Etoh的摄入对病毒感染后胰腺的病理效应的影响。这一模型系统的开发和表征将提供一个有用的酒精性胰腺炎模型，使后续研究能够探索乙醇增敏胰腺损伤的机制。该模型系统还将允许对可能的治疗干预进行批判性研究。

DESCRIPTION (provided by applicant): A large proportion of the cases of pancreatitis in human beings are associated with alcohol consumption, but pancreatitis develops in only a minority of people who abuse alcohol. These observations support the argument that factors other than alcohol or alcohol metabolisms are involved in the development of alcoholic pancreatitis. The hypothesis that will be investigated by the research proposed in this exploratory/developmental grant application is that one co-factor for the development of acute and chronic alcoholic pancreatitis is an infection with a virus that has a tropism for the pancreas. This viral infection is hypothesized to initiate the damage in the pancreas and this damage is more severe in individuals who abuse alcohol through an alcohol-associated sensitization of the pancreas. A murine model of alcohol consumption that is done with the use of C57BL/6 and Balb/c mice provided ethanol (ETOH) in either a liquid diet or in the drinking water will be used for these studies. Specifically, mice provided ETOH and control mice (i.e., pair-fed and chow-fed) will be infected with coxsackievirus group B, stereotype 3 (CVB3) and pancreas damage and fibrosis will be evaluated. The hypotheses will be addressed by three specific aims: 1) To develop the model system to characterize the effects of ETOH and CVB3 infection of the pancreas; 2) To determine the effect of ETOH consumption on production of pro-inflammatory cytokines during the viral infection; 3) To determine the effects of chronic ETOH consumption, with an ETOH-in-drinking-water model system, on pathologic effects in the pancreas after viral infection. The development and characterization of this model system will provide a useful model of alcoholic pancreatitis that will allow follow-up studies to investigate mechanisms of ETOH to sensitize the pancreas to damage. The model system will also allow critical studies of possible therapeutic interventions.