基于PSMP/CCR2轴调控肝内Ly6C(hi)/Ly6C(lo)巨噬细胞平衡研究益肝消积方干预早期肝硬化的作用机制

肝硬化是严重危害生命健康的常见病，缺少逆转方案。最新研究表明，PSMP/CCR2轴能调控肝内Ly6C(hi)/Ly6C(lo)巨噬细胞平衡，进而上调TGF-β1表达，增加肝星状细胞活化，促进肝硬化发生发展。申请人前期研究证实益肝消积方治疗早期肝硬化疗效确切，并能通过下调TGF-β1表达抑制肝星状细胞活化。因此提出科学假说：益肝消积方通过调控PSMP/CCR2轴，减少单核细胞来源巨噬细胞肝内募集，影响肝内Ly6C(hi)/Ly6C(lo)巨噬细胞平衡，从而逆转早期肝硬化。本研究采用四氯化碳复制早期肝硬化模型，明确益肝消积方对肝内Ly6C(hi)/Ly6C(lo)巨噬细胞平衡及其上游PSMP/CCR2轴的调控作用，同时运用Rescue实验原理及巨噬细胞过继转移、腺相关病毒载体感染等技术加以验证，从而揭示益肝消积方干预早期肝硬化疏肝健脾、除湿化痰、活血解毒的作用机制，为临床推广应用提供科学依据。

Liver cirrhosis is a common disease which does great harm to health, while no reversion treatment is available. Recent studies have shown that PSMP/CCR2 axis regulates the balance of Ly6C(hi)/Ly6C(lo) macrophages in liver, and then increases the expression of TGF-β1, promoting the activation of hepatic stellate cells. This mechanism finally causes and accelerates the development of liver cirrhosis. The applicant's previous researches have demonstrated the effect of Yigan Xiaoji Decoction on early cirrhosis. The decoction inhibited the activation of hepatic stellate cells by down regulating the expression of TGF-β1. Therefore, the scientific hypothesis is put forward, which is that Yigan Xiaoji Decoction may reduce the recruitment of monocyte derived macrophages in liver and target PSMP/CCR2 axis regulating the balance of Ly6C(hi)/Ly6C(lo) macrophages in liver, so as to reverse early liver cirrhosis. In this study, carbon tetrachloride will be used to replicate the model of early liver cirrhosis, to clarify the regulatory effect of Yigan Xiaoji Decoction on the balance of Ly6C(hi)/Ly6C(lo) macrophages in liver and PSMP/CCR2 axis. At the same time, to reveal the mechanism of Yigan Xiaoji Decoction, the rescue experimental principle, macrophage adoptive transfer experiment, and adeno-associated virus vector infection will also be applied to verify the scientific hypothesis. The results of this study will provide scientific basis for the clinical application of Yigan Xiaoji Decoction.