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

缺血后处理作为保护肝脏的新策略：NLRP3 炎性体介导的途径在库普弗细胞中的作用

基本信息

批准号：
223988225
负责人：
Dr. Christian Steib
金额：
--
依托单位：
Medizinische Klinik und Poliklinik II - Großhadern
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2012
资助国家：
德国
起止时间：
2011-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/223988225?language=en
关键词：
Ischemic postconditioning novel strategy protect

项目摘要

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.

肝脏缺血再灌注损伤（IRI）对于接受肝移植或切除的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，导致边缘器官移植给MELD评分高的患者。这种不利的情况导致肝移植后的结果更差。因此，有必要研究IRI的发病机制，并开发新的治疗策略。一种简单易行的治疗策略已在心脏病中得到广泛测试：缺血后处理。缺血后处理是指手术后即刻出现短暂的缺血和短暂的复流。初步结果首次证明缺血后处理对肝脏有保护作用。因此，更详细地研究这种干预似乎是很有意义的。此外，正在审议国际注册机构的机制。最近，NLRP3炎性体途径已被描述在对乙酰氨基酚诱导的肝损伤中。NLRP 3炎性体可以被病原体相关分子模式（PAMP）和损伤相关分子模式（DAMP）激活。众所周知，这些分子模式的流入参与IRI。因此，研究IRI中的NLRP 3炎性体通路以潜在开发新的靶向治疗似乎是主要的兴趣。已知库普弗细胞的激活参与IRI，并且库普弗细胞可以通过分子模式激活。因此，对库普弗细胞中NLRP3通路的研究是一个合乎逻辑的结果。总之，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NLRP 3炎性体通路。