Review
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastrointest Pharmacol Ther. Feb 6, 2017; 8(1): 10-25
Published online Feb 6, 2017. doi: 10.4292/wjgpt.v8.i1.10
Pathogenic mechanisms of pancreatitis
Murli Manohar, Alok Kumar Verma, Sathisha Upparahalli Venkateshaiah, Nathan L Sanders, Anil Mishra
Murli Manohar, Alok Kumar Verma, Sathisha Upparahalli Venkateshaiah, Nathan L Sanders, Anil Mishra, Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, New Orleans, LA 70112, United States
Author contributions: Manohar M drafted the manuscript and prepared all figures; Verma AK, Venkateshaiah SU and Sanders NL contributed and critically reviewed the manuscript; Mishra A designed, conceived and provided financial assistance.
Supported by National Institutes of Health, Nos. R01 DK067255 and R01 AI080581.
Conflict-of-interest statement: All authors declare no conflict of interests for this review.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Anil Mishra, PhD, Endowed Chair and Professor of Medicine, Department of Medicine, Section of Pulmonary Diseases, Tulane Eosinophilic Disorders Center, Tulane University School of Medicine, SL-9, 1430, Tulane Avnue, New Orleans, LA 70112, United States. amishra@tulane.edu
Telephone: +1-504-9883840 Fax: +1-504-9882144
Received: June 8, 2016
Peer-review started: June 13, 2016
First decision: July 20, 2016
Revised: July 23, 2016
Accepted: August 15, 2016
Article in press: August 16, 2016
Published online: February 6, 2017
Processing time: 226 Days and 12.5 Hours
Abstract

Pancreatitis is inflammation of pancreas and caused by a number of factors including pancreatic duct obstruction, alcoholism, and mutation in the cationic trypsinogen gene. Pancreatitis is represented as acute pancreatitis with acute inflammatory responses and; chronic pancreatitis characterized by marked stroma formation with a high number of infiltrating granulocytes (such as neutrophils, eosinophils), monocytes, macrophages and pancreatic stellate cells (PSCs). These inflammatory cells are known to play a central role in initiating and promoting inflammation including pancreatic fibrosis, i.e., a major risk factor for pancreatic cancer. A number of inflammatory cytokines are known to involve in promoting pancreatic pathogenesis that lead pancreatic fibrosis. Pancreatic fibrosis is a dynamic phenomenon that requires an intricate network of several autocrine and paracrine signaling pathways. In this review, we have provided the details of various cytokines and molecular mechanistic pathways (i.e., Transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) that have a critical role in the activation of PSCs to promote chronic pancreatitis and trigger the phenomenon of pancreatic fibrogenesis. In this review of literature, we discuss the involvement of several pro-inflammatory and anti-inflammatory cytokines, such as in interleukin (IL)-1, IL-1β, IL-6, IL-8 IL-10, IL-18, IL-33 and tumor necrosis factor-α, in the pathogenesis of disease. Our review also highlights the significance of several experimental animal models that have an important role in dissecting the mechanistic pathways operating in the development of chronic pancreatitis, including pancreatic fibrosis. Additionally, we provided several intermediary molecules that are involved in major signaling pathways that might provide target molecules for future therapeutic treatment strategies for pancreatic pathogenesis.

Keywords: Pancreatitis; Pancreatic stellate cells; Transforming growth factor-β/SMAD; Janus kinase/signal transducers and activators; Mitogen-activated protein kinases

Core tip: Pancreatitis is an acute or chronic inflammatory disease of the pancreas and characterized by destruction of acinar cells, which lead activation of several inflammatory cells like macrophages and granulocytes which secrete number of pro-inflammatory cytokines. These pro-inflammatory cytokines activate pancreatic stellate cells, i.e., the key cells of pancreatic fibrosis. Various molecular signaling pathways (i.e., transforming growth factor-β/SMAD, mitogen-activated protein kinases, Rho kinase, Janus kinase/signal transducers and activators, and phosphatidylinositol 3 kinase) are known to have critical role in the activation of pancreatic stellate cells in chronic pancreatitis and development of pancreatic fibrosis that lead to the pancreatic carcinoma.