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Cholinergic Mediation of Alcohol-Induced Experimental Pancreatitis

Authors

  • Aurelia Lugea,

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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  • Jun Gong,

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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  • Janie Nguyen,

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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  • Jose Nieto,

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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  • Samuel W. French,

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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  • Stephen J. Pandol

    1. From the USC-UCLA Research Center for Alcoholic Liver and Pancreatic Diseases (AL, JG, JN, JN, SJP), Veterans Affairs Greater Los Angeles Healthcare System and University of California, Los Angeles, California; and Department of Pathology (SWF), Harbor-UCLA Medical Center, Torrance, California.
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Reprint requests: Aurelia Lugea, PhD, Veterans Affairs Greater Los Angeles Healthcare System, Building 258, room 339, 11301 Wilshire Blvd, Los Angeles, CA 90073; Tel.: 310-478-3711; Fax: 310-268-4578; E-mail: alugea@ucla.edu

Abstract

Objectives:  The mechanisms initiating pancreatitis in patients with chronic alcohol abuse are poorly understood. Although alcohol feeding has been previously suggested to alter cholinergic pathways, the effects of these cholinergic alterations in promoting pancreatitis have not been characterized. For this study, we determined the role of the cholinergic system in ethanol-induced sensitizing effects on cerulein pancreatitis.

Methods:  Rats were pair-fed control and ethanol-containing Lieber-DeCarli diets for 6 weeks followed by parenteral administration of 4 hourly intraperitoneal injections of the cholecystokinin analog, cerulein at 0.5 μg/kg. This dose of cerulein was selected because it caused pancreatic injury in ethanol-fed but not in control-fed rats. Pancreatitis was preceded by treatment with the muscarinic receptor antagonist atropine or by bilateral subdiaphragmatic vagotomy. Measurement of pancreatic pathology included serum lipase activity, pancreatic trypsin, and caspase-3 activities, and markers of pancreatic necrosis, apoptosis, and autophagy. In addition, we measured the effects of ethanol feeding on pancreatic acetylcholinesterase activity and pancreatic levels of the muscarinic acetylcholine receptors m1 and m3. Finally, we examined the synergistic effects of ethanol and carbachol on inducing acinar cell damage.

Results:  We found that atropine blocked almost completely pancreatic pathology caused by cerulein administration in ethanol-fed rats, while vagotomy was less effective. Ethanol feeding did not alter expression levels of cholinergic muscarinic receptors in the pancreas but significantly decreased pancreatic acetylcholinesterase activity, suggesting that acetylcholine levels and cholinergic input within the pancreas can be higher in ethanol-fed rats. We further found that ethanol treatment of pancreatic acinar cells augmented pancreatic injury responses caused by the cholinergic agonist, carbachol.

Conclusion:  These results demonstrate key roles for the cholinergic system in the mechanisms of alcoholic pancreatitis.

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