Scientific paper Bile-pancreatic juice exclusion increases cholinergic M3 and CCK-A receptor expression and interleukin-6 production in ligation-induced acute pancreatitis Isaac Samuel, M.D., F.R.C.S., F.A.C.S. a, *, Asgar Zaheer, Ph.D. a , Smita Zaheer, Ph.D. b , Rory A. Fisher, Ph.D. c a Department of Surgery, Veterans Affairs Medical Center & University of Iowa Roy J. and Lucille A. Carver College of Medicine, 200 Hawkins Dr., 4625 JCP, Iowa City, IA 52242, USA b Department of Surgery, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA c Department of Pharmacology, University of Iowa Roy J. and Lucille A. Carver College of Medicine, Iowa City, IA, USA Manuscript received June 10, 2004; revised manuscript July 7, 2004 Presented at the 28th Annual Symposium of the Association of VA Surgeons, Richmond, Virginia, April 25–27, 2004 Abstract Background: Using an original model, the Donor Rat Model, we showed that bile-pancreatic juice (BPJ) exclusion from gut exacerbates ligation-induced acute pancreatitis in rats. We also showed that muscarinic cholinergic M3 and CCK-A receptor expression is induced following duct ligation. Increased receptor number potentially could exacerbate cytokine production. We hypothesize that BPJ exclusion is responsible for M3 and CCK-A receptor induction and increased interleukin-6 (IL-6) production. Methods: M3 and CCK-A receptor expression and IL-6 production were compared in rat pancreata 1 to 3 hours after duct ligation with or without BPJ replacement. Results: Our studies showed that BPJ replacement attenuates duct ligation–induced increases in M3 and CCK-A receptor expression and IL-6 production. Conclusions: In this model, BPJ exclusion from gut induces M3 and CCK-A receptor expression and increases IL-6 production. In this experimental corollary of gallstone pancreatitis, BPJ exclusion from gut may play a key role in the mechanism of disease pathogenesis. © 2004 Excerpta Medica Inc. All rights reserved. Keywords: Acute pancreatitis; donor rat model; CCK-A receptor; cholinergic M3 receptor; cytokines; interleukin-6 Using a unique and original surgical model, the Donor Rat Model, we previously showed that BPJ exclusion from gut exacerbates duct ligation–induced acute pancreatitis in rats [1]. By use of specific receptor antagonists to muscarinic cholin- ergic M3 and CCK-A receptors, we suggested that the mech- anism of this effect may involve M3 and CCK-A receptor pathways [2,3]. Interestingly, we found that ligation-induced acute pancreatitis is associated with increases in M3 and CCK-A receptor expression [4,5]. It is possible that increased expression of these receptors could amplify bile-pancreatic juice (BPJ) exclusion-induced exocrine pancreatic hyperstimu- lation and thus exacerbate pancreatic production of proinflam- matory cytokines such as interleukin-6 (IL-6). Therefore, we hypothesized that BPJ exclusion is responsible for M3 and CCK-A receptor induction and exacerbation of pancreatic IL-6 production in ligation-induced acute pancreatitis. In the present study, we test our hypothesis by examining the effects of BPJ replacement on ligation-induced acute pancreatitis using the Donor Rat Model. Our results show that duodenal replacement of BPJ (obtained fresh from a donor rat) attenuates duct liga- tion–induced increases in pancreatic M3 and CCK-A receptor expression and IL-6 production. In this experimental corollary of gallstone pancreatitis, BPJ exclusion from gut may play a key role in the mechanism of disease pathogenesis. Supported by an American College of Surgeons Faculty Research Fellowship and a National Institutes of Health NIDDK Career Develop- ment Award (Grant K08-DK062805) to I.S. * Corresponding author. Tel.: 1-319-384-7220; fax: 1-319-356- 8378. E-mail address: Isaac-samuel@uiowa.edu The American Journal of Surgery 188 (2004) 511–515 0002-9610/04/$ – see front matter © 2004 Excerpta Medica Inc. All rights reserved. doi:10.1016/j.amjsurg.2004.07.008