Matrix metalloproteinase inhibition protects rat livers from prolonged cold ischemia-warm reperfusion injury.
- Others:
- Institut de pharmacologie moléculaire et cellulaire (IPMC) ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Centre National de la Recherche Scientifique (CNRS)
- Signalisation moléculaire et obésité ; Université Nice Sophia Antipolis (1965 - 2019) (UNS) ; COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-IFR50-Institut National de la Santé et de la Recherche Médicale (INSERM)
- Service de Chirurgie Digestive / Centre de Transplantation Hépatique [CHU Nice] ; Centre Hospitalier Universitaire de Nice (CHU Nice)
- Département d'Ingénierie et Etudes des Protéines ; Commissariat à l'énergie atomique et aux énergies alternatives (CEA)
- Centre de Recherche du Centre Hospitalier Universitaire de Montréal ; Centre Hospitalier de l'Université de Montréal (CHUM) ; Université de Montréal (UdeM)-Université de Montréal (UdeM)
- Service d'Anatomie et Cytologie Pathologiques ; Hôpital Pasteur [Nice] (CHU)
- Laboratory of Organic Chemistry
- Fédération d'Hépato-Gastroentérologie ; Hôpital Archet II
Description
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). CONCLUSION: 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.
Additional details
- URL
- https://hal.archives-ouvertes.fr/hal-00315635
- URN
- urn:oai:HAL:hal-00315635v1
- Origin repository
- UNICA