高血糖激活Kupffer细胞ATF6-CHOP通路在肝脏缺血再灌注损伤中的作用及其机制

糖尿病(Diabetes Mellitus，DM)是肝移植供体和受体术前常见的伴发疾病，前期已证实高血糖或DM可增加肝脏缺血再灌注损伤(Ischemia Reperfusion Injury，IRI)相关炎症，恶化肝脏IRI，严重影响肝移植预后，但确切机制研究尚不清楚。内质网应激(Endoplasmic Reticulum Stress，ERS)是重要的代谢性应激，在肝脏IRI炎症反应中发挥关键性作用。预实验显示高血糖或DM可特异性激活肝组织及肝内Kupffer细胞(KCs)的ERS相关信号ATF6-CHOP通路，采用ERS抑制剂处理可缓解高血糖或DM相关肝脏IRI炎症反应。因此，该项目假设“高血糖特异性激活KCs的ATF6-CHOP通路，促进KCs活化，加重炎症反应，恶化肝脏IRI”，并分析其确切机制。本项目的实现将为临床高血糖或DM相关肝脏IRI的防治提供新思路和理论依据。

Diabetes mellitus (DM) is a common concomitant disease in donors and recipients of liver transplantation. Previous study has been proved that hyperglycemia or DM markedly increases inflammatory responses, strongly worsens liver IRI, seriously affects prognosis of liver transplantation, but the exact mechanisms is unclear. Endoplasmic reticulum stress (ERS), an important metabolic stress, plays critical roles in inflammatory responses and during liver IRI. Preliminary experiments showed that hyperglycemia or DM specially activated ERS-related ATF6-CHOP pathway in liver tissue and Kupffer cells (KCs); pretreatment of ERS inhibitor effectively inflammatory responses related hyperglycemia or DM during liver IRI. Herein, we suppose that hyperglycemia or DM specially triggers ATF6-CHOP of KCs, and increases inflammatory responses, and worsens liver IRI. In addition, we will investigate exact mechanisms of the hypothesis. The success of the project will provide the rationale for novel therapeutic strategies aimed at managing diabetic/ hyperglycemia -related liver surgery.