Basic Study
Copyright ©The Author(s) 2016. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jun 7, 2016; 22(21): 4988-4998
Published online Jun 7, 2016. doi: 10.3748/wjg.v22.i21.4988
Multiorgan chronic inflammatory hepatobiliary pancreatic murine model deficient in tumor necrosis factor receptors 1 and 2
Helieh S Oz
Helieh S Oz, Department of Physiology and Internal Medicine, College of Medicine, University of Kentucky Medical Center, Lexington, KY 40536, United States
Author contributions: Oz HS designed and executed the study, prepared the paper and provided funding; author has approved the final paper.
Supported by The NIH grant R03-DE019177.
Institutional animal care and use committee statement: All animal procedures were approved by the University of Kentucky Institutional animal care and use committee.
Conflict-of-interest statement: Author declares to have no commercial or associative interest that represents a conflict of interest in connection with the work submitted.
Data sharing statement: No additional data are available.
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: Helieh S Oz, DVM, PhD, AGAF, Department of Physiology and Internal Medicine, College of Medicine, University of Kentucky Medical Center, Lexington, KY 40536, United States. hoz2@email.uky.edu
Telephone: +1-859-2770988 Fax: +1-859-3231000
Received: January 15, 2016
Peer-review started: January 18, 2016
First decision: February 18, 2016
Revised: March 21, 2016
Accepted: April 7, 2016
Article in press: April 7, 2016
Published online: June 7, 2016
Processing time: 136 Days and 1.3 Hours
Abstract

AIM: To provoke persistent/chronic multiorgan inflammatory response and to contribute to stones formation followed by fibrosis in hepatobiliary and pancreatic tissues.

METHODS: Tumor necrosis factor receptors 1 and 2 (TNFR1/R2) deficient mice reared in-house were given dibutyltin dichloride (DBTC) twice within 10 d by oral gavage delivery. Sham control animals received vehicle treatment and naïve animals remained untreated throughout the study. Animals were monitored daily for symptoms of pain and discomfort. The abdominal and hindpaw hypersensitivity were assessed with von Frey microfilaments. Exploratory behaviors were recorded at the baseline, after initiation of treatment, and before study termination. Histopathological changes were examined postmortem in tissues. Collagen accumulation and fibrosis were confirmed with Sirius Red staining.

RESULTS: Animals lost weight after oral administration of DBTC and developed persistent inflammatory abdominal and hindpaw hypersensitivity compared to sham-treated controls (P < 0.0001). These pain related secondary mechanical hypersensitivity responses increased more than 2-fold in DBTC-treated animals. The drastically diminished rearing and grooming rates persisted after DBTC administration throughout the study. Gross as well as micropathology at one month confirmed that animals treated with DBTC developed chronic hepatobiliary injuries evidenced with activation of stellate cells, multifocal necrosis, fatty degeneration of hepatocytes, periportal infiltration of inflammatory cells, and prominent biliary ductal dilation. The severity of hepatitis was scored 3.7 ± 0.2 (severe) in DBTC-treated animals vs score 0 (normal) in sham-treated animals. Fibrotic thickening was extensive around portal ducts, in hepatic parenchyma as well as in lobular pancreatic structures and confirmed with Sirius Red histopathology. In addition, pancreatic microarchitecture was presented with distortion of islets, and parenchyma, infiltration of inflammatory cells, degeneration, vacuolization, and necrosis of acinar cells and distention of pancreatic ducts. Extent of pancreatic damage and pancreatitis were scored 3.6 ± 0.4 (severe) for DBTC-treated in contrast to score 0 (normal) in sham-treated animals. The gall bladder became expanded with ductal distention, and occasional bile stones were detected along with microscopic hepatic lesions. DBTC-treated animals developed splenic hypertrophy with increased weight and length (P < 0.01) along with thymic atrophy (P < 0.001). Finally, colitic lesions and colitis were prominent in DBTC-treated animals and scored 3.4 ± 0.3 (moderately severe) vs 0 (normal) for the sham-treated animals.

CONCLUSION: This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, along with fibrosis and calculi formation induced reliably utilizing oral DBTC administration in TNFR1/R2 deficient mice.

Keywords: Inflammatory pain; Multiorgan; Hepatitis; Pancreatitis; Calculi formation; Gall bladder; Hepatobiliary inflammation

Core tip: Currently there is no reliable model for chronic multiorgan inflammatory and fibrosis. Tumor necrosis factor (TNF)α initiates inflammation through TNFR1/R2. TNFR1/R2 deficient mice administered orally with dibutyltin dichloride (DBTC) developed significant persistent inflammatory and pain related secondary mechanical hypersensitivity. DBTC-animals showed severe chronic hepatobiliary injuries and prominent biliary ductal dilation. Extensive fibrotic thickening was evidenced around portal ducts, in hepatic and pancreatic structures. DBTC-animals had severe pancreatic damage and pancreatitis, hepatic lesions with expansion of gall bladder, bile stones and severe colitis. This is the first report of chronic inflammatory multiorgan hepatobiliary pancreatitis, fibrosis and calculi formation in TNFR1/R2 deficient mice.