Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury.
Matrix metalloproteinases (MMPs) have been implicated in the hepatic injury induced after cold ischemia-warm reperfusion (CI-WR), by altering the extracellular matrix (ECM), but their precise role remains unknown. The hepatic MMP expression was evaluated after 2 conditions of CI (4 degrees C for 24 and 42 hours: viable and nonviable livers) followed by different periods of WR, using isolated perfused rat livers. CI-WR induced moderate changes in hepatic MMP transcript levels not influenced by CI duration, whereas gelatinase activities accumulated in liver effluents. Therefore, the protective effect of a new phosphinic MMP inhibitor, RXP409, was tested after prolonged CI. RXP409 (10 microM) was added to the University of Wisconsin solution, and livers were preserved for 42 hours (4 degrees C), then reperfused for 1 hour in Krebs solution (37 degrees C), containing 20% erythrocytes. Liver viability parameters were recorded, and the extent of cell necrosis was evaluated on liver biopsies, using trypan blue nuclear uptake. Treatment with RXP409 significantly improved liver function (transaminase release and bile secretion) and liver injury. In particular, the MMP inhibitor significantly modified the extent of cell death from large clusters of necrotic hepatocytes as found in control livers (2%-60% of liver biopsies; mean, 26% +/- 9%) to isolated necrotic hepatocytes as found in treated livers (0.2%-12%; mean, 3% +/- 2%) (P < 0.05).


CONCLUSIONS
These data demonstrate that MMPs, by altering the ECM, play a major role in liver CI-WR injury leading to extensive hepatocyte necrosis and that their inhibition might prove to be a new strategy in improving preservation solutions.
Defamie
Virginie
V
Institut de Pharmacologie Moléculaire et Cellulaire, CNRS, UMR6097, Université de Nice-Sophia Antipolis, France.
Laurens
Marina
M
Patrono
Damiano
D
Devel
Laurent
L
Brault
Antoine
A
Saint-Paul
Marie-Christine
MC
Yiotakis
Athanasios
A
Barbry
Pascal
P
Gugenheim
Jean
J
Crenesse
Dominique
D
Dive
Vincent
V
Huet
Pierre-Michel
PM
Mari
Bernard
B
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D050377:Cold Ischemia / Q000009:adverse effects*; D042783:Endothelial Cells / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D005353:Fibronectins / Q000378:metabolism; D015870:Gene Expression; D022781:Hepatocytes / Q000187:drug effects; D008107:Liver Diseases / Q000201:enzymology* / Q000378:metabolism; D008297:Male; D061965:Matrix Metalloproteinase Inhibitors; D020782:Matrix Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D009336:Necrosis / Q000517:prevention & control; D010721:Phosphinic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000201:enzymology* / Q000378:metabolism / Q000517:prevention & control; D013997:Time Factors; D019714:Tissue Inhibitor of Metalloproteinases / Q000235:genetics / Q000378:metabolism*; D014022:Tissue Survival / Q000187:drug effects; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use
D004791:Enzyme Inhibitors; D005353:Fibronectins; D061965:Matrix Metalloproteinase Inhibitors; D010721:Phosphinic Acids; C526977:RXP 409; D019714:Tissue Inhibitor of Metalloproteinases; D014364:Tryptophan; D020782:Matrix Metalloproteinases