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Rat liver injury following normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor
Author(s) -
Cursio Raffaele,
Mari Bernard,
Louis Krystel,
Rostagno Philippe,
Saint-Paul Marie-Christine,
Giudicelli Jean,
Bottero Virginie,
Anglard Patrick,
Yiotakis Athanasios,
Dive Vincent,
Gugenheim Jean,
Auberger Patrick
Publication year - 2002
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.01-0279fje
Subject(s) - matrix metalloproteinase , gelatinase a , ischemia , medicine , liver injury , liver transplantation , matrix metalloproteinase inhibitor , pathology , gelatinase , necrosis , collagenase , hepatocyte , tissue inhibitor of metalloproteinase , transplantation , endocrinology , biology , enzyme , biochemistry , in vitro
Hepatic ischemia occurs in liver transplantation, hemodynamic or cardiogenic shock, and liver resection associated with trauma or tumor. Ischemia/reperfusion (I/R) injury results in microcirculation failure followed by apoptosis and necrosis. Matrix metalloproteinases (MMPs) are involved in many physiological and pathological processes, but their expression and function during liver I/R remains poorly documented. In this study, we evaluated the expression of nine MMPs and their natural inhibitors, tissue inhibitors of MMPs (TIMPs), in a rat model of liver I/R. Analysis of MMP and TIMP expression show that although most of these genes are not constitutively expressed in the normal liver, they are induced in a specific time‐dependent manner following I/R. Stromelysin‐1, gelatinase B, and collagenase‐3 are induced during the early phase of acute liver injury associated with inflammation and increased necrosis/apoptosis, whereas gelatinase A, membrane type‐MMP, stromelysin‐3, metalloelastase, TIMP‐1, and TIMP‐2 are essentially detectable during the recovery phase of liver injury corresponding to hepatocyte regeneration. This observation suggested that MMPs and TIMPs could play both deleterious and beneficial roles following I/R. We thus tested the effect of a specific phosphinic MMP inhibitor on acute liver I/R injury. Inhibition of MMP activity was shown to significantly decrease liver injury in ischemic/reperfused liver tissue as assessed by histological studies and serum hepatic enzyme levels. We therefore propose that MMP inhibitors may be of clinical relevance in liver‐associated ischemic diseases or after liver transplantation.