Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Nov 14, 2015; 21(42): 12114-12124
Published online Nov 14, 2015. doi: 10.3748/wjg.v21.i42.12114
Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury: A review
Giuseppina Palladini, Andrea Ferrigno, Plinio Richelmi, Stefano Perlini, Mariapia Vairetti
Giuseppina Palladini, Andrea Ferrigno, Plinio Richelmi, Stefano Perlini, Mariapia Vairetti, Department of Internal Medicine and Therapeutics, University of Pavia, 27100 Pavia, Italy
Author contributions: Palladini G and Vairetti M wrote the final version; Palladini G, Ferrigno A, Perlini S and Vairetti M wrote the draft versions; Ferrigno A contributed to data acquisition; Richelmi P revised and edited the draft versions; all authors approved the final version of the paper.
Supported by Fondazione Cariplo, No. 2011-0439.
Conflict-of-interest statement: Authors declare no conflict of interest.
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:
Correspondence to: Mariapia Vairetti, PhD, Department of Internal Medicine and Therapeutics, University of Pavia, Via Ferrata 9A, 27100 Pavia, Italy.
Telephone: +39-382-986398 Fax: +39-382-986347
Received: March 20, 2015
Peer-review started: March 22, 2015
First decision: April 13, 2015
Revised: April 28, 2015
Accepted: September 30, 2015
Article in press: September 30, 2015
Published online: November 14, 2015

Matrix metalloproteinases (MMPs) are a family of proteases using zinc-dependent catalysis to break down extracellular matrix (ECM) components, allowing cell movement and tissue reorganization. Like many other proteases, MMPs are produced as zymogens, an inactive form, which are activated after their release from cells. Hepatic ischemia/reperfusion (I/R) is associated with MMP activation and release, with profound effects on tissue integrity: their inappropriate, prolonged or excessive expression has harmful consequences for the liver. Kupffer cells and hepatic stellate cells can secrete MMPs though sinusoidal endothelial cells are a further source of MMPs. After liver transplantation, biliary complications are mainly attributable to cholangiocytes, which, compared with hepatocytes, are particularly susceptible to injury and ultimately a major cause of increased graft dysfunction and patient morbidity. This paper focuses on liver I/R injury and cholestasis and reviews factors and mechanisms involved in MMP activation together with synthetic compounds used in their regulation. In this respect, recent data have demonstrated that the role of MMPs during I/R may go beyond the mere destruction of the ECM and may be much more complex than previously thought. We thus discuss the role of MMPs as an important factor in cholestasis associated with I/R injury.

Keywords: Matrix metalloproteinases, Liver, Ischemia/reperfusion, Cholestasis

Core tip: Induction of matrix metalloproteinases (MMPs) modulates the progression of liver damage such as ischemia/reperfusion (I/R) injury and acute allograft rejection. The high incidence of biliary complications, after liver transplantation, is due to a cascade of events leading to biliary lesions to which cholangiocytes are particularly susceptible. This paper, while focusing on liver I/R and cholestasis, reviews factors and mechanisms implicated in MMP activation/regulation together with the role of MMPs in biliary complications following I/R injury. Recent data support the view that MMPs play a dual role, both good and bad, in liver I/R depending on the length of time after damage.