Ischemic postconditioning as novel strategy to protect the liver: Role of NLRP3 inflammasome-mediated pathways in Kupffer cells

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Ischemia-reperfusion injury (IRI) of the liver is an unresolved issue for patients undergoing liver transplantation or resection. The increasing gap between patients on the waiting list and available organs results in the transplantation of marginal organs to patients with a high MELD score. This unfavourable situation leads to a worse outcome following liver transplantation. Therefore it is necessary to investigate the mechanisms of IRI and to develop new therapeutic strategies. An easy to perform therapeutic strategy has been tested widely in heart diseases: ischemic postconditioning. Ischemic postconditioning is defined as brief periods of ischemia alternating with brief periods of reflow immediately after the surgical procedure. Preliminary own results give first evidence that ischemic postconditioning is protective for the liver. It seems therefore of major interest to investigate this intervention more in detail. Furthermore, the mechanisms of IRI are under consideration. Recently, the NLRP3 inflammasome pathway has been described in acetaminophen-induced liver injury. The NLRP3 inflammasome can be activated by pathogen associated molecular patterns (PAMP’s) and damage associated molecular patterns (DAMP’s). It is well known that the inflow of these molecular patterns is involved in IRI. It seems therefore of major interest to investigate the NLRP3 inflammasome pathway in IRI for the potential development of new targeted therapies. The activation of Kupffer cells is known to be involved in IRI and Kupffer cells can be activated by molecular patterns. The investigation of the NLRP3 pathway in Kupffer cells therefore is a logical consequence. In summary, this project aims to investigate the protective effect of ischemic postconditioning to reduce IRI and the potentially involved NLRP3 inflammasome pathway.