FAS siRNA donor administration has the potential to alleviate ischemia-reperfusion injury in an arterialized rat liver transplant model

Bonaccorsi Riani, Eliano [UCL] Iesari, Samuele [UCL] Komuta, Mina [UCL] Gillooly, AR Bozorgzadeh, A Gianello, Pierre [UCL] Martins, PN

Background: Liver ischemia-reperfusion injury (IRI) is an inherent pathological process occurring in liver transplantation, which compromises graft, and patient outcomes. The degree of apoptosis is associated with IRI intensity. We hypothesized that silencing of apoptosis-associated genes can alleviate IRI leading to better graft and liver recipients survival rates. Methods: Male Lewis rats were transplanted with a syngeneic liver graft employing an arterialized rat liver transplantation model. A prolonged cold ischemia time (CIT) of 22 hours was established in order to amplify the intensity of the IRI, reflected by the post-transplant transaminases levels. We administered 500ng of FAS siRNA diluted in 1 ml of PBS via the penile vein in donors rats (siRNA-treated group) two hours before the aorta cross clamping. Donors in the control group (Control) received an injection of PBS alone in the same conditions. Blood samples were collected daily until the euthansia at day 3 post-transplant. Results: We performed an initial experiment with 4 animals in each group. All animals survived until day 3 post-transplant. CIT (siRNA-treated: 1293±54min x 1330±60min Control, p=0.39) and anhepatic time (siRNA-treated: 17.00±0,5min x 16.25±1.18min Control, p=0.395) were comparable between the two groups. Recipients of siRNA-treated liver grafts showed lower levels of transaminases on the first day post transplantation with a trend to be statistically significant: AST (siRNA-treated x Control: 1074.00±621.23 IU/L x 2194.50±945 IU/L respectively, p=0.053) and ALT (siRNA-treated x Control: 734.00±464.15IU/L x 1929.50±1344 IU/L respectively, p=0.061). The histological analysis following the Suzuki criteria showed similar IRI damage in both groups. Conclusion: Our preliminary results suggest that silencing of apoptosis-associated genes could be used to alleviate post liver transplantation IRI. Further experiments are necessary to corroborate this therapeutic strategy. Next, we are going to test FAS siRNA organ treatment during liver machine perfusion. (Graph Presented).