基于调控肺泡Ⅱ型上皮细胞自噬和肺成纤维细胞糖酵解探讨益气破瘀消痰法治疗IPF配伍分层作用和整体优势效应研究

Idiopathic pulmonary fibrosis (IPF) is a challenging problem in clinical treatment. Autophagy deficiency regulated by Akt/mTOR axis in typeⅡalveolar epithelial cells (AECⅡ) and augmented glycolysis mediated by TGF-β1/Smad axis in lung fibroblasts (FB) lead to the AECⅡ repair and regeneration ability dysfunction and enhanced proliferation and differentiation of lung FB, both of them promote the progression of IPF. Our research group found Yiqipoyuxiaotan therapy was effective in the treatment of IPF. Combining with our previous work, we hypothesize Yiqipoyuxiaotan Chinese medicine could enhance the repair and regeneration of AECⅡ and inhibit the proliferation and differentiation of lung FB by regulating the key targets of the AECⅡ autophagy deficiency and the lung FB augmented glycolysis, so as to treat IPF. Compatibility parts of Yiqi and Poyuxiaotan are able to play the specific roles of promoting autophagy and suppressing glycolysis respectively, and the two parts could enhance autophagy and inhibit glycolysis collaboratively. We will apply the technologies of gene knockout and siRNA transfection into the researches in vivo and in vitro in this project, in order to explore the therapeutic mechanism of Yiqipoyuxiaotan therapy in treating IPF patients. The project results could help us delineate the separated compatibility effects and the overall synergistic advantages of Yiqipoyuxiaotan therapy, in order to explain the meaning of the prescription composition and provide theoretical and experimental basis for the clinical application and the scientific connotation development of Yiqipoyuxiaotan therapy in IPF.

特发性肺纤维化（IPF）的治疗是临床中迫切需要解决的重大难题。肺泡Ⅱ型上皮细胞（AECⅡ）Akt/mTOR轴调节的自噬不足和肺成纤维细胞（FB）TGF-β1/Smad轴介导的糖酵解升高是AECⅡ修复及再生功能障碍和肺FB增殖分化增强的重要机制，共同促进IPF形成。课题组发现益气破瘀消痰法可有效治疗IPF，结合前期基础提出该法中药复方通过调控AECⅡ自噬不足和肺FB糖酵解增强机制中关键靶点，提高AECⅡ修复及再生能力，抑制肺FB增殖分化以治疗IPF。配伍分层“益气”和“破瘀消痰”两部分分别发挥“促自噬”和“抑糖酵解”的特异性作用，两者可形成“促自噬+抑糖酵解”的整体效应。项目拟结合基因敲除和siRNA转染等技术开展体内外研究，从整体到微观逐步揭示益气破瘀消痰法治疗IPF作用机制，明确其配伍分层作用和整体优势效应，阐释其组方内涵，为提升其临床应用价值和丰富其现代科学内涵提供理论基础和实验依据。

特发性肺纤维化（IPF）的治疗是临床中迫切需要解决的重大难题。肺泡Ⅱ型上皮细胞（AECⅡ）Akt/mTOR调节自噬不足和肺成纤维细胞（FB）TGF-β1/Smad介导糖酵解升高是AECⅡ修复及再生功能障碍和肺FB增殖分化增强的重要机制，共同促进IPF形成。本项目研究发现益气破瘀消痰法中药复方可通过调控AECⅡ自噬不足和肺FB糖酵解增强机制中的关键靶点，提高AECⅡ修复及再生能力，抑制肺FB增殖分化以有效治疗IPF，其中配伍分层“益气”和“破瘀消痰”两部分分别发挥“促自噬”和“抑糖酵解”的特异性作用，两者可形成“促自噬+抑糖酵解”的整体效应。研究揭示了益气破瘀消痰法治疗IPF的作用机制，明确了其配伍分层作用和整体协同性优势效应，阐释了其组方内涵，为提升其临床应用价值和丰富其现代科学内涵提供了理论基础和实验依据。