A ROLE FOR VIRAL INFECTION IN ALCOHOLIC PANCREATITIS

描述（由申请人提供）： 人类胰腺炎的大部分病例与饮酒有关，但胰腺炎仅发生在少数滥用酒精的人中。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。本探索性/发展性资助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展的一个辅助因素是感染了对胰腺有向性的病毒。假设这种病毒感染会引发胰腺损伤，并且这种损伤在酗酒者中通过酒精相关的胰腺致敏作用而更加严重。使用C57 BL/6和Balb/c小鼠完成的酒精消耗小鼠模型将用于这些研究，所述小鼠在液体饮食或饮用水中提供乙醇（ETOH）。具体地，提供ETOH的小鼠和对照小鼠（即，配对喂养和食物喂养）感染柯萨奇病毒组B，定型3（CVB 3），并评价胰腺损伤和纤维化。 该假说将通过三个具体目标来解决：1）开发表征ETOH和CVB 3感染胰腺的作用的模型系统; 2）确定病毒感染期间ETOH消耗对促炎细胞因子产生的作用; 3）为了确定慢性ETOH消耗的影响，使用饮用水中的ETOH模型系统，对病毒感染后胰腺的病理影响。该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，这将允许后续研究调查ETOH的机制，使胰腺对损伤敏感。该模型系统还将允许对可能的治疗干预进行关键研究。

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.