IL-18诱导胰腺星状细胞中FKN上调在慢性胰腺炎中的作用和机制研究

Chronic pancreatitis(CP) is a clinical refractory disease with resistance to cure, when it reaches the advanced stage, the patients will present with diabetes, exocrine insufficiency or pancreatic cancer, which will affect their quality of life seriously. As we all know, pancreatic fibrosis is one of the most typical histopathological features, but there are not any effective treatments available for it.Fractalkine（FKN）is the only known member of the CX3C chemokine subclass, which can promote adhesion and aggregation of inflammatory cells and play an important role in the formation of pancreatic fibrosis.At the same time, interleukin-18 is a novel proinflammatory cytokin, which can upregulate FKN expression in some endothelial cells. Before this, we have already estasblished animal models of CP induced by DBTC and mastered the skills of purifying and culturing pancreatic stellate cell(PSC) . Our preliminary study confirmed that FKN and CX3CR1 was up-regulated both at the mRNA and protein levels in the pancreas of CP rats.In this study, we will go further to prove that IL-18 could activate quiescent PSC and upregulate FKN expression in PSC by means of RT-PCR, Western Blot and the like. We will also do the research on the signal conducting pathway such as NF-kB. In a word, we aim to find out the modifying system of pancreatic fibrosis and the molecular mechanism of pancreatic fibrosis, to diversify the pathogenesis of pancreatic fibrosis and to provide a new way for the treatment of CP.

慢性胰腺炎（CP）是一种迁延不愈、临床难治性疾病，晚期可进展为糖尿病、胰腺外分泌功能不全或胰腺癌，严重影响患者生活质量，其主要病理学特征是胰腺纤维化，但目前尚无有效干预措施。Fractalkine（FKN）是CX3C家族中唯一已知的趋化因子，它可以促进炎症细胞的粘附和聚集，参与胰腺纤维化的形成。同时，IL-18作为一种促炎症因子，可以显著上调内皮细胞中FKN的表达。我们前期研究成功构建了二丁基二氯化锡诱导CP纤维化动物模型并分离和原代培养了胰腺星状细胞（PSC），且发现CP模型的胰腺组织中FKN和CX3CR1显著上调。本研究拟通过RT-PCR、Western Blot等技术，证实IL-18可以诱导PSC发生活化并显著上调PSC中FKN的表达，同时检测NF-kB信号转导通路相关基因和蛋白表达，明确其调控胰腺纤维化的分子机制，丰富胰腺纤维化机制研究，为抑制或逆转胰腺纤维化提供新的治疗靶点。

慢性胰腺炎（CP）主要病理学特征是胰腺纤维化。趋化因子Fractalkine（FKN）可以促进炎症细胞的粘附和聚集，参与胰腺纤维化的形成。同时，IL-18作为一种促炎症因子，可以显著上调内皮细胞中FKN的表达。本研究主要证实IL-18可以诱导PSC发生活化并显著上调PSC中FKN的表达。本课题主要研究内容：1.鉴定静息、活化PSC中IL-18和FKN表达差异；2.验证IL-18上调PSC表达FKN的作用；3.探索IL-18上调PSC表达FKN的作用机制。主要研究结果有：1.造模组CP大鼠胰腺组织IL-18和FKN表达高于对照组正常大鼠；2.造模组CP大鼠PSC表达IL-18和FKN高于正常对照组；3.体外实验IL-18能激活人胰腺星状细胞，并上调FKN表达。4.PDTC不能缓解IL-18引起的人PSC激活和FKN上调。本研究为抑制或逆转胰腺纤维化提供新的治疗靶点。