紫檀芪基于肝脏微环境调控NK-HSCs相互作用改善肝纤维化进程的研究

肝纤维化是多种慢性肝脏疾病向肝硬化发展的必经阶段，及时阻断肝纤维化有助于病情转归。前期研究发现紫檀芪(PTE)调控肝纤维化进程、诱导活化肝星状细胞(HSCs)凋亡，同时有助于激活自然杀伤（NK）细胞。基于此，拟从肝脏微环境中NK-HSCs出发，探究PTE在自身抑制HSC活化基础上，明确激活NK细胞可能是PTE基于肝脏微环境调控肝纤维化的有效途径。通过肝纤维化小鼠、NK耗竭小鼠和RAG2-/-小鼠肝纤维化模型、肝纤维化小鼠肝脏NK细胞和HSCs细胞、以及NK-HSCs细胞共培养模型，观察PTE调控NK-HSCs细胞改善肝纤维化的作用和关键药理机制；以JAK1-SHP-1为PTE调控NK-HSCs细胞信号通路中的共同关键位点，采用siRNA和过表达技术寻求PTE在NK细胞和HSCs细胞中具体信号通路以及相互影响的调控机制，为肝纤维化治疗寻找具有明确作用靶点的、安全有效的药物提供可靠的理论依据。

Hepatic fibrosis is an unavoidable stage of many chronic liver diseases to liver cirrhosis, and inhibiting the progression of hepatic fibrosis would be benefit for disease outcome. Our previous study found that Pterostilbene (PTE) could regulate hepatic fibrosis and induce apoptosis of activated HSCs; also found PTE could contribute to the activation of NK cells. Based on the above, the study intends to explore that PTE activates NK cells and inhibits HSC activation in liver microenvironment, which may be an effective way for PTE to regulate hepatic fibrosis. The hepatic fibrosis model of C57BL/6 mice, NK exhaustion mice and RAG2-/- mice, hepatic NK cells and HSCs cells from hepatic fibrosis mice, and NK-HSCs co-cultured model in vitro, are adopted to observe the regulation of PTE in NK-HSCs cell function and the key pharmacological mechanism in amelioration of hepatic fibrosis. Considering JAK1-SHP-1 signaling as the common key sites, siRNA and overexpression techniques are used to seek the specific signaling pathway, interactions and regulatory mechanisms in NK and HSCs cells with PTE incubation. The study would supply theoretical basis for seeking anti-hepatic fibrosis drug with a clearly defined target and safe and effective character.