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

肝脏缺血再灌注损伤(IRI)对肝移植或肝切除患者来说是一个尚未解决的问题。等待名单上的患者与可用器官之间的差距越来越大，导致边缘器官移植到MELD评分较高的患者。这种不利的情况导致了肝移植后更糟糕的结果。因此，有必要对IRI的发病机制进行研究，并开发新的治疗策略。一种易于实施的治疗策略已经在心脏病中得到了广泛的测试：缺血后处理。缺血后处理的定义是外科手术后短暂的缺血和短暂的复流交替出现。自己的初步结果首次证明，缺血后处理对肝脏具有保护作用。因此，更详细地调查这种干预似乎是一件很有意义的事情。此外，正在考虑IRI的机制。最近，NLRP3炎症体通路在扑热息痛诱导的肝损伤中被描述。NLRP3炎症体可被病原体相关分子模式(PAMP‘s)和损伤相关分子模式(DAMP’s)激活。众所周知，这些分子模式的流入参与了IRI。因此，研究IRI中的NLRP3炎症体通路对于开发新的靶向治疗具有重要意义。Kupffer细胞的激活被认为与IRI有关，Kupffer细胞可以通过分子模式被激活。因此，研究Kupffer细胞中的NLRP3通路是合乎逻辑的结果。综上所述，本项目旨在研究缺血后处理对减少IRI的保护作用以及可能涉及的NLRP3炎症小体通路。

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.