Journal
AMERICAN JOURNAL OF TRANSPLANTATION
Volume 8, Issue 9, Pages 1819-1828Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1600-6143.2008.02336.x
Keywords
apoptosis; c-Jun N-terminal kinase 2; ischemia/reperfusion injury; liver transplantation; mitochondrial permeability transition; necrosis; storage/reperfusion injury; survival
Categories
Funding
- NATIONAL CENTER FOR RESEARCH RESOURCES [C06RR015455] Funding Source: NIH RePORTER
- NATIONAL INSTITUTE OF DIABETES AND DIGESTIVE AND KIDNEY DISEASES [R37DK037034, R01DK037034, R01DK070844, R56DK037034, R01DK073336] Funding Source: NIH RePORTER
- NCRR NIH HHS [C06 RR015455] Funding Source: Medline
- NIDDK NIH HHS [DK73336, R01 DK037034, R37 DK037034-22, R56 DK037034, R01 DK037034-23, DK37034, R37 DK037034, R01 DK070844, R01 DK073336, R01 DK073336-02, DK70844] Funding Source: Medline
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The c-Jun N-terminal kinase (JNK) pathway enhances graft injury after liver transplantation (LT). We hypothesized that the JNK2 isoform promotes graft injury via the mitochondrial permeability transition (MPT). Livers of C57BL/6J (wild-type, WT) and JNK2 knockout (KO) mice were transplanted into WT recipients after 30 h of cold storage in UW solution. Injury after implantation was assessed by serum ALT, histological necrosis, TUNEL, Caspase 3 activity, 30-day survival, and cytochrome c and 4-hydroxynonenal immunostaining. Multiphoton microscopy after LT monitored mitochondrial membrane potential in vivo. After LT, ALT increased three times more in WT compared to KO (p < 0.05). Necrosis and TUNEL were more than two times greater in WT than KO (p < 0.05). Immunostaining showed a > 80% decrease of mitochondrial cytochrome c release in KO compared to WT (p < 0.01). Lipid peroxidation was similarly decreased. Every KO graft but one survived longer than all WT grafts (p < 0.05, Kaplan-Meier). After LT, depolarization of mitochondria occurred in 73% of WT hepatocytes, which decreased to 28% in KO (p < 0.05). In conclusion, donor JNK2 promotes injury after mouse LT via the MPT. MPT inhibition using specific JNK2 inhibitors may be useful in protecting grafts against adverse outcomes from ischemia/reperfusion injury.
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