Role of matrix metalloproteinases in cholestasis and hepatic ischemia/reperfusion injury: A review

Table 1 Classification and characteristics of the main matrix metalloproteinases

MMP (class and number)	Name	Extracellular Matrix substrate
Collagenases
MMP-1	Collagenase 1	Collagen I, II, III, VII, VIII and X, gelatin, proteoglycans, tenascin, entactin
MMP-8	Collagenase 2	Collagen I, II, III, V, VIII and X, gelatin, aggrecan
MMP-13	Collagenase 3	Collagen I, II, III, IV, IX and X, fibronectin, gelatin, tenascin, aggrecan, osteonectin
Gelatinases
MMP-2	Gelatinase A	Collagen I, IV, V, VII, IX and X, gelatin, proteoglycans, elastin, fibronectin, laminin, aggrecan, versican, osteonectin
MMP-9	Gelatinase B	Collagen IV, V, VII, X and XIV, gelatin, proteoglycans, elastin, aggrecan, versican, osteonectin
Stromelysins
MMP-3	Stromelysins 1	Collagen III, IV, V, and IX, gelatin, proteoglycans, tenascin, fibronectin, laminin, aggrecan, versican, osteonectin
MMP-10	Stromelysins 2	Collagen III, IV and V, gelatin, proteoglycans, aggrecan, elastin, casein
MMP-11	Stromelysins 3	Collagen IV, fibronectin, laminin, gelatin, transferrin
Membrane type
MMP-14	MT1-MMP	Collagen I, II and III, fibronectin, vitronectin, tenascin, laminin, proteoglycans, aggrecan, elastin, casein, entactin
MMP-15	MT2-MMP	Fibronectin, tenascin, laminin
MMP-16	MT3-MMP	Collagen III, fibronectin, casein, gelatin
MMP-17	MT4-MMP	ND
MMP-24	MT5-MMP	Activator of proMMP-2
MMP-25	MT6-MMP	Collagen IV, fibronectin, gelatin, fibrinogen
Others
MMP-7		Collagen IV and X, gelatin, proteoglycans, tenascin, fibronectin, laminin, aggrecan, osteonectin, entactin, casein, tranferrin, integrin b4
MMP-12		Collagen IV, gelatin, proteoglycans, fibronectin, laminin, entactin, casein, vibronectin, elastin
MMP-19	ND	Aggrecan, cartilage oligomeric matrix protein (COMP)
MMP-20	Enamelysin	Amelogenin
MMP-23A	MMP-21	ND
MMP-23B	MMP-22	ND
MMP-26	Matrilysin 2	Collagen IV, fibronectin, casein, fibrinogen
MMP-27	ND	ND
MMP-28	Epilysin	Casein

ND: Not Determined; MMP: Matrix metalloproteinase.

Table 2 Synthetic compounds involved in matrix metalloproteinase regulation

Compounds	Mechanism involved	MMPs involved	I/R model	Ref.
Bortezomib	Downregulation of pro-inflammatory (IL-1β, TNF-α and IFN-γ) and pro-fibrotic (VEGF, TGF-β, HGF, bFGF) factors	MMP-2MMP-9	Steatotic orthotopic liver transplant	Tiriveedhi et al[45],Transpl Immunol 2014
KMUP-1 (NO-donor)	Protects from apoptosis-associated free radical generation and pro-inflammation	MMP-9	Hypoxic HepG2 cells	Kuo et al[90], Int J Imm Pharm 2013
CS-1 peptide	Blocks fibronectin α4β1 and decreases the release of pro-inflammatory mediators	MMP-9MT-1-MMP/MMP-14	Cold ischemia	Duarte et al[91],Am J Transpl 2012
CTT peptide	Reduction in TNF-α, IL-1, IL-2 and IFN-γ	MMP-9	Acute small-for-size liver graft	Ma et al[34], Am J Transpl 2010
Cyclic RGD peptide	Depresses inflammatory mediators (IFN-γ)	MMP-9	Steatotic Cold ischemia	Fondevila et al[92],Am J Transpl 2009
ONO-1714	iNOS inhibitor	MMP-9	Warm ischemia	Hamada et al[46], Am J Pathol 2009
RXP409	Inhibitory effects on MMP activity	MMPs	Cold ischemia	Defamie et al[28],Hepatology 2008
Anti-MMP-9	Decrease in expression of TNF-α, IL-2 and IFN-γ	MMP-9	Warm ischemia	Hamada et al[23], Hepatology 2008
CS-1 peptide	Blocks FN α4β1 integrin and its FN ligand	MMP-9	Steatotic orthotopic liver transplant	Moore et al[29], Am J Pathol 2007
ONO-4817	Reduction in TNF-α, IL-1β	MMP-2 and MMP-9	Warm ischemia	Shirahane et al[33],Surgery 2006
NAC	Reduction in free radicals	MMP-9	Warm ischemia	Chen et al[93], Transpl Proc 2005
BB3103	Prostaglandin PGE(1) protection	MMP-2	Cold ischemia	Yang et al[94], Microvasc Res 2002
RXPO3	Protects from necrosis/apoptosis	MMP-3-9-11-13	Warm ischemia	Cursio et al[24], FASEB J 2002

MMP: Matrix metalloproteinase; CS-1: Connecting segment-1; FN: Fibronectin; TNF-α: Tumor necrosis factor; TGF-β: Transforming growth factor β; IFN: Interferon; iNOS: Inducible nitric oxide synthase; IL: Interleukin.

Table 3 Endogenous factors associated with matrix metalloproteinase modulation

Factors	MMPs Involved	I/R Model	Ref.
FN-α-β1	MMP-9MT1-MMP/MMP-14	Cold ischemia	Duarte et al[91], Am J Transpl 2012
			Coito[48], Curr Opin Organ Transplant 2011
			Moore et al[29], Am J Pathol 2007
			Fondevilla et al[95], Transplant Proc 2005
			Amersi et al[47], Am J Pathol 2003
Tenascin-C	MMP-9	Warm ischemia	Kuriyama et al[96], Hepatology 2011
iNOS	MMP-9	Warm ischemia	Hamada et al[46], Am J Pathol 2009
TNF-α	MMP-2 and MMP-9	Warm ischemia	Feng et al[39], J Surg Res 2013
			Palladini et al[43], Toxicol and Pathol 2012
			Khandoga et al[26], J Leukoc Biol 2006
			Chen et al[93], Transplant Proc 2005
IL-1β	MMP-2 and MMP-9	Warm ischemia	Shirahane et al[33], Surgery 2006
IL-6	MMP-9	Warm ischemia	Hamada et al[46], Am J Pathol 2009
IFNα-2a	MMP-2 and MMP-9	Cholestasis	Bueno et al[54], J Hepatol 2000
CD62	MMP-2 and MMP-9	Warm ischemia	Khandoga et al[26], J Leukoc Biol 2006
Plasmin	MMP-9	Cholestasis	Martínez-Rizo et al[97], Liver Int 2010
TGF-β	MMP-9	Warm ischemia	Feng et al[39], J Surg Res 2013
	MMP-13	Cholestasis	Aldaba-Muruato et al[98], Can J Physiol Pharmacol 2012
IL-10	MMP-2 and MMP-9	Warm ischemia	Feng et al[99], Int Immunopharmacol 2012

MMP: Matrix metalloproteinase; TNF-α: Tumor necrosis factor; iNOS: Inducible nitric oxide synthase; IL: Interleukin; IFNα-2a: Interferon α- 2a; TGF-β: Transforming growth factor β; FN: Fibronectin.