Resumen de New strategies to reduce liver ischemia – reperfusion injury in fatty and non-fatty livers: a focus on sirtuin 1 implication
Eirini Pantazi
Ischemia-reperfusion injury (IRI) is an inevitable situation in clinical settings such as liver transplantation and hepatic resection. It develops when blood flow is interrupted for a long period of time (ischemia) and then it restarts (reperfusion). IRI pathophysiology is highly complex and includes a number of mechanisms, such as oxidative stress, inflammation, apoptosis, microcirculatory disturbances, that contribute to organ damage and limit the clinical outcome. In addition, in order to reduce the gap between the need and availability of donors, many transplantation teams now use liver grafts, that previously have been considered unsuitable for transplantation, such as the steatotic livers. Steatotic livers are characterized by an excessive lipid accumulation and present higher vulnerability against IRI in comparison to normal ones. Subsequently, the use of steatotic liver grafts has been associated with poorest transplantation outcome and higher incidence of dysfunction. In spite of the extensive investigations, IRI remains an unsolved problem and it is necessary the identification of new targets that could mitigate its adverse effects. Recently, sirtuin 1, (SIRT1) a nicotinamide adenosine dinucleotide (NAD+)-dependent deacetylase has gained increasing attention from researchers, due to its involvement in various cellular functions, including cell response to stress, cell cycle and metabolism. Although SIRT1 has been associated with beneficial effects against IRI in heart and brain, no data have been reported concerning its potential implication in hepatic IRI and liver transplantation. Consequently, the present thesis aims to investigate the potential role of SIRT1 in rat liver IRI in a model of warm ischemia-reperfusion in steatotic livers (first study), in a model of rat orthotopic liver transplantation, OLT, (second study) and in reduced-size orthotopic liver transplantation, ROLT, (third study). In the first study, SIRT1 has been associated with the beneficial effects of ischemic preconditioning (a well-known surgical strategy to prevent IRI). In rat OLT SIRT1 has been correlated with the activation of autophagic pathway. In ROLT SIRT1 has been shown to contribute to the beneficial effects exerted by angiotensin II inhibition. According these results, the present thesis concludes that SIRT1 is implicated in the hepatic IRI and that strategies that enhance its activity can be a promising approach to reduce liver IRI.
