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Surgical Procedures for a Rat Model of Partial Orthotopic Liver Transplantation with Hepatic Arterial Reconstruction
Published on: March 7, 2013
c-Jun N-terminal kinase mediates hepatic injury after rat liver transplantation
Tetsuya Uehara1, Xing Xi Peng, Brydon Bennett
1Department of Medicine, University of North Carolina at Chapel Hill, USA.
Background:
Orthotopic liver transplantation (OLT) requires cold ischemic storage followed by warm reperfusion. Although c-Jun N-terminal kinase (JNK) is rapidly activated after OLT, the functional consequences of JNK activation are unknown. The aim of this study was to address the role of JNK after OLT using the selective JNK inhibitor CC-401.
Methods:
Donors, recipients, or stored liver explants were treated with vehicle or JNK inhibitor before OLT by an arterialized two-cuff method with 40 hours of cold storage. Recipients were assessed for 30-day survival, and graft injury was assessed over time by hepatic histology, serum transaminases, caspase 3 activation, cytosolic cytochrome c, and lipid peroxidation.
Results:
Survival after OLT increased after donor plus storage and storage only treatment with JNK inhibitor (P<0.05). Treatment of recipient only did not improve survival. Increased survival correlated with improved hepatic histology and serum aspartate aminotransferase levels. JNK inhibition significantly decreased nonparenchymal cell killing at 60 minutes after reperfusion (P<0.05) and pericentral necrosis at 8 hours after reperfusion (P<0.01). JNK inhibition decreased cytochrome c release, caspase 3 activation (P<0.05), and lipid peroxidation (P<0.05). JNK inhibition also transiently blocked phosphorylation of c-Jun at 60 minutes after reperfusion (P<0.05) without affecting other MAPK signaling, including p-38 and Erk activation.
Conclusions:
JNK inhibition decreases hepatic necrosis and apoptosis after OLT, suggesting that JNK activation promotes cell death by both pathways. Inhibition of JNK may be a new therapeutic strategy to prevent liver injury after transplantation.
Insights
Inhibition of c-Jun N-terminal kinase (JNK) improves survival after liver transplantation by reducing cell death. This finding suggests JNK inhibition as a novel therapeutic strategy for preventing organ damage.
Area of Science:
- Hepatology
- Transplantation Immunology
- Molecular Medicine
Background:
- Orthotopic liver transplantation (OLT) involves cold storage and warm reperfusion, leading to rapid c-Jun N-terminal kinase (JNK) activation.
- The precise role of JNK activation in OLT-induced injury remains unclear.
Purpose of the Study:
- To investigate the functional consequences of JNK activation post-OLT.
- To evaluate the therapeutic potential of the selective JNK inhibitor CC-401 in preventing liver injury after OLT.
Main Methods:
- OLT was performed using an arterialized two-cuff method with 40 hours of cold storage.
- Donors, recipients, or stored liver explants were treated with vehicle or CC-401.
- Outcomes assessed included 30-day survival, hepatic histology, serum transaminases, and markers of apoptosis and lipid peroxidation.
Main Results:
- JNK inhibition significantly increased 30-day survival when applied to donors or stored grafts, but not recipients alone.
- CC-401 treatment reduced hepatic necrosis and apoptosis, evidenced by improved histology, lower transaminase levels, and decreased caspase 3 activation and lipid peroxidation.
- JNK inhibition specifically blocked c-Jun phosphorylation without impacting other MAPK pathways.
Conclusions:
- JNK activation exacerbates hepatic injury after OLT through both necrosis and apoptosis.
- Inhibiting JNK offers a promising therapeutic approach to mitigate liver damage and improve outcomes in liver transplantation.
