肝脏缺血再灌注损伤(Ischemia-reperfusion injury，IRI)是一个复杂的病理生理过程，导致肝脏IRI的因素很多，其中炎症反应起关键作用，确切机制尚不清楚。研究证实Toll样受体4(Toll like receptor 4，TLR4)参与肝脏IRI，本组证实内质网应激(Endoplasmic reticulum stress，ERS)协同TLR4参与肝脏IRI，其机制有待进一步研究。预实验显示热缺血可以直接激活Kupffer细胞，提高TLR4的反应性，促进炎症反应。有趣的是，缺血阶段三条ERS通路仅ATF6被激活，且ERS抑制剂或ATF6siRNA预处能理明显抑制缺血激活TLR4。该项目将研究该假设"缺血激活ATF6协同TLR4促进炎症反应，增加肝脏IRI损伤程度"，且分析其确切机制。本项目的实现对缺血性疾病具有一定的普遍意义，且为肝脏IRI提供新的分子治疗靶点。

Liver ischemia reperfusion injury (IRI) is a complex Pathophysiological processes. Many factors, especially inflammatory responses, can lead to liver IRI, but the exact pathogenesis is not very clear. Studies indicated that Toll-like receptor 4 (TLR4) was involved in hepatic IRI. Our group has demonstrated that endoplasmic reticulum stress (ERS) has a synergy with TLR4 during liver IRI, but the exact mechanisms need be further investigated. Our previous experiments have showed that ischemia directly activates Kupffer cells, enhances reactivity of Kupffer cells to TLR4 ligand (LPS), strengthen inflammatory responses. Interestingly, our pre-experiments also indicated that only ATF6 pathway was activated in three ERS pathways during ischemia. In addition, an ERS inhibitor (or ATF6siRNA)significantly reduced activation of TLR4 induced by ischemia. Herein, we suppose that ATF6 activation triggered by ischemia has a synergy with TLR4 innate immune responses and increased liver IRI; and further investigate exact mechanisms of this hypothesis. The success of the project will be an important significance in ischemia diseases, and provide a new target to molecular therapy of liver IRI.