Rat liver injury after normothermic ischemia is prevented by a phosphinic matrix metalloproteinase inhibitor.
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.
Cursio
Raffaele
R
Laboratoire de Recherches Chirurgicales, IFR50, France.
Mari
Bernard
B
Louis
Krystel
K
Rostagno
Philippe
P
Saint-Paul
Marie-Christine
MC
Giudicelli
Jean
J
Bottero
Virginie
V
Anglard
Patrick
P
Yiotakis
Athanasios
A
Dive
Vincent
V
Gugenheim
Jean
J
Auberger
Patrick
P
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008107:Liver Diseases / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D008115:Liver Regeneration; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism; D009336:Necrosis; D010721:Phosphinic Acids / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D015427:Reperfusion Injury / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control*; D013696:Temperature; D019714:Tissue Inhibitor of Metalloproteinases / Q000096:biosynthesis / Q000235:genetics
D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids; D012333:RNA, Messenger; D019714:Tissue Inhibitor of Metalloproteinases; D020782:Matrix Metalloproteinases