Oncotarget

Research Papers: Pathology:

Binge ethanol exposure causes endoplasmic reticulum stress, oxidative stress and tissue injury in the pancreas

Zhenhua Ren, Xin Wang, Mei Xu, Fanmuyi Yang, Jacqueline A. Frank, Zun-ji Ke and Jia Luo _

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Oncotarget. 2016; 7:54303-54316. https://doi.org/10.18632/oncotarget.11103

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Abstract

Zhenhua Ren1,2, Xin Wang2, Mei Xu2, Fanmuyi Yang2, Jacqueline A. Frank2, Zun-ji Ke3 and Jia Luo2,3

1 Department of Anatomy, School of Basic Medicine, Anhui Medical University, Hefei, China

2 Department of Pharmacology and Nutritional Sciences, University of Kentucky College of Medicine, Lexington, Kentucky, USA

3 Department of Biochemistry, Shanghai University of Traditional Chinese Medicine, Shanghai, China

Correspondence to:

Jia Luo, email:

Keywords: apoptosis, glucose, inflammation, insulin, pancreatitis, Pathology Section

Received: May 10, 2016 Accepted: July 19, 2016 Published: August 05, 2016

Abstract

Alcohol abuse is associated with both acute and chronic pancreatitis. Repeated episodes of acute pancreatitis or pancreatic injury may result in chronic pancreatitis. We investigated ethanol-induced pancreatic injury using a mouse model of binge ethanol exposure. Male C57BL/6 mice were exposed to ethanol intragastrically (5 g/kg, 25% ethanol w/v) daily for 10 days. Binge ethanol exposure caused pathological changes in pancreas demonstrated by tissue edema, acinar atrophy and moderate fibrosis. Ethanol caused both apoptotic and necrotic cell death which was demonstrated by the increase in active caspase-3, caspase-8, cleaved PARP, cleaved CK-18 and the secretion of high mobility group protein B1 (HMGB1). Ethanol altered the function of the pancreas which was indicated by altered levels of alpha-amylase, glucose and insulin. Ethanol exposure stimulated cell proliferation in the acini, suggesting an acinar regeneration. Ethanol caused pancreatic inflammation which was indicated by the induction of TNF-alpha, IL-1beta, IL-6, MCP-1 and CCR2, and the increase of CD68 positive macrophages in the pancreas. Ethanol-induced endoplasmic reticulum stress was demonstrated by a significant increase in ATF6, CHOP, and the phosphorylation of PERK and eiF-2alpha. In addition, ethanol increased protein oxidation, lipid peroxidation and the expression of iNOS, indicating oxidative stress. Therefore, this paradigm of binge ethanol exposure caused a spectrum of tissue injury and cellular stress to the pancreas, offering a good model to study alcoholic pancreatitis.


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