Abstract 1249: Animal model in the prevention of alcoholic pancreatitis

2018 
Background: Alcohol abuse is a major risk factor for pancreatitis. Alcohol addiction-induced molecular pathogenesis of pancreatitis remains obscure, and no current effective treatment exists. Therefore, approaches to investigate pathogenesis, prevention and cellular mechanisms by which alcohol causes pancreatitis are necessary for establishing therapeutics. Our efforts demonstrate that alcohol induces activation of a major intracellular transcriptional factor, cyclic AMP response element-binding protein (CREB). We further investigated the functional role of CREB in alcohol-induced pathogenesis of pancreatitis using cellular and genetic mouse models of pancreas. Materials and Methods: Human tissue microarrays were immunostained to determine the significance of pCREB expression among pancreatic tissues obtained from normal and chronic pancreatitis. Rat acinar cell line AR42J and mouse PSCs (mPSCs) were exposed to alcohol (50 mMol/L). Inducible Ptf1aCreERTM knockin mice and Ptf1aCreERTM;CREBfl/fl (iPC) mice were fed with Lieber Decarli diet alcohol or regular diet for 14 weeks with or without caerulein (50 µg/kg). Mice were then euthanized 24 hours after the last caerulein injection, and pancreas tissues were processed for morphometric analysis (necrosis, vacuolization, hemorrhage, edema and inflammation) and immunohistochemical analysis of amylase, trichrome blue, SMA, collagen 1, fibronectin and pCREB expression. To determine whether alcohol accelerated morbidity in mice, we evaluated pathogenesis of chronic pancreatitis by analyzing acinar atrophy and pancreatic fibrosis. Results: Expression of pCREB was significantly higher (p Conclusion: CREB is overexpressed in pancreatitis and alcohol activates CREB, which then drives pathogenesis of pancreatitis. Severity of pancreatitis in response to alcohol is diminished in the absence of CREB. Therefore, we conclude that targeting CREB represents a promising treatment for alcohol-induced pancreatitis. Citation Format: Supriya Srinivasan, Tulasigeri Totiger, Michael VanSaun, Fanuel Messaggio, Chanjuan Shi, Austin Dosch, Eric Nestler, Nipun Merchant, Nagaraj Nagathihalli. Animal model in the prevention of alcoholic pancreatitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 1249.
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