Original Article
Copyright ©2011 Baishideng Publishing Group Co., Limited. All rights reserved.
World J Gastrointest Pathophysiol. Dec 15, 2011; 2(6): 146-154
Published online Dec 15, 2011. doi: 10.4291/wjgp.v2.i6.146
Stimulation of oval cell and hepatocyte proliferation by exogenous bombesin and neurotensin in partially hepatectomized rats
Stelios F Assimakopoulos, Athanassios C Tsamandas, Ilias H Alexandris, Christos Georgiou, Constantine E Vagianos, Chrisoula D Scopa
Stelios F Assimakopoulos, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece
Athanassios C Tsamandas, Chrisoula D Scopa, Department of Pathology, University Hospital of Patras, Patras 26504, Greece
Ilias H Alexandris, Department of Surgery, General Hospital of Amfissa, Amfissa 33100, Greece
Christos Georgiou, Department of Biology, Section of Genetics, Cell Biology and Development, University of Patras, Patras 26100, Greece
Constantine E Vagianos, 1st Department of Surgical, “Saint Panteleimon” General Hospital of Nikaia, Piraeus 18454, Greece
Author contributions: Assimakopoulos SF, Vagianos CE andScopa CD contributed to the conception and design; Alexandris IH, Georgiou C and Tsamandas AC contributed to the acquisition of data; Tsamandas AC and Assimakopoulos SF analyzed and interrelated the data; Assimakopoulos SF drafted the manuscript; Vagianos CE and Scopa CD critically revised the manuscript; all the authors have read and approved the final version of the manuscript.
Correspondence to: Stelios F Assimakopoulos, MD, PhD, Department of Internal Medicine, University Hospital of Patras, Patras 26504, Greece. sassim@upatras.gr
Telephone: +30-2610-999583 Fax: +30-2610-993982
Received: September 26, 2011
Revised: November 7, 2011
Accepted: November 14, 2011
Published online: December 15, 2011
Abstract

AIM: To investigate the effect of the neuropeptides bombesin (BBS) and neurotensin (NT) on oval cell proliferation in partially hepatectomized rats not pretreated with a known hepatocyte inhibitor.

METHODS: Seventy male Wistar rats were randomly divided into five groups: I = controls, II = sham operated, III = partial hepatectomy 70% (PHx), IV = PHx + BBS (30 μg/kg per day), V = PHx + NT (300 μg/kg per day). Forty eight hours after liver resection, portal endotoxin levels and hepatic glutathione redox state were determined. α-fetoprotein (AFP) mRNA (in situ hybridisation), cytokeratin-19 and Ki67 antigen expression (immunohistochemistry) and apoptosis (TUNEL) were evaluated on liver tissue samples. Cells with morphological features of oval cells that were cytokeratin-19 (+) and AFP mRNA (+) were scored in morphometric analysis and their proliferation was recorded. In addition, the proliferation and apoptotic rates of hepatocytes were determined.

RESULTS: In the control and sham operated groups, oval cells were significantly less compared to groups III, IV and V (P < 0.001). The neuropeptides BBS and NT significantly increased the proliferation of oval cells compared to group III (P < 0.001). In addition, BBS and NT induced a significant increase of hepatocyte proliferation (P < 0.001), whereas it decreased their apoptotic activity (P < 0.001) compared to group III. BBS and NT significantly decreased portal endotoxemia (P < 0.001) and increased the hepatic GSH: GSSG ratio (P < 0.05 and P < 0.001, respectively) compared to group III.

CONCLUSION: BBS and NT stimulated oval cell proliferation in a model of liver regeneration, without use of concomitant suppression of hepatocyte proliferation as oval cell activation stimuli, and improved the hepatocyte regenerative response. This peptides-induced combined stimulation of oval cell and hepatocyte proliferation might serve as a possible treatment modality for several liver diseases.

Keywords: Liver regeneration; Partial hepatectomy; Hepatic progenitor cells; Oval cells; Apoptosis; Proliferation; Oxidative stress