白介素17A抑制自噬活性促进组织纤维化发生发展

发布时间：2018-04-25 04:22

本文选题：白介素17A + 组织纤维化　；参考：《北京协和医学院》2012年博士论文

【摘要】：组织重构性疾病已成为全球范围内最严重的公共卫生问题之一。全球每年死亡人口中有超过45%是因为罹患各种组织重构性疾病。组织纤维化是组织重构性疾病的典型病理改变,也是多种慢性疾病的核心病理改变,直接导致了慢性疾病的久治不愈迁延反复。组织纤维化的发生发展机制并不十分清楚。现有研究表明,多种信号通路如Smads和β-catenin等参与介导组织纤维化相关分子表达。肌成纤维细胞活化是组织纤维化发生发展的细胞生物学基础。损伤发生时,多种细胞在不同刺激如TGF-β1、IL-6等下化生为肌成纤维细胞,活化并合成和释放大量胶原等细胞外基质,参与组织纤维化发生发展。慢性炎症局部免疫微环境的性质决定了炎症的性质,而病灶局部炎症的性质是决定组织纤维化相关疾病预后的关键。研究表明,以Th2为主的抑制性免疫微环境加剧组织纤维化的发生发展,而Thl型免疫微环境却能够改善组织纤维化病理状况。Th17型细胞是独立于Th1/2的一种新近被鉴别出来的T辅助细胞亚型。其主要效应因子IL-17A被认为在多种炎症相关疾病和自身免疫病中发挥重要作用。我们推测IL-17A也参与了组织纤维化的发生发展。我们首先在动物和细胞水平对IL-17A与组织纤维化的相关性进行研究。研究结果表明,IL-17A能够诱导促纤维化因子TGF-β1分泌,促进上皮细胞发生EMT反应,诱导肌成纤维细胞活化,合成和分泌胶原。同时,在博来霉素诱导的小鼠肺纤维化、胆总管结扎诱导的小鼠肝纤维化和腹主动脉缩窄诱导的小鼠心肌纤维化组织中,IL-17A的表达水平显著升高。接着,我们使用抗IL-17A中和性抗体对多种纤维化疾病模型小鼠进行治疗学研究。实验结果表明,阻断IL-17A能够显著改善博来霉素或二氧化硅诱导的小鼠肺纤维化、胆总管结扎诱导的小鼠肝纤维化和腹主动脉缩窄诱导的小鼠心肌纤维化并改善纤维化组织局部炎症状况,调节炎症性质向有利于纤维化消退的方向进行。我们最近发现自噬作为TLR4活化的效应机制,能够促进慢性炎症转归进而改善急性肺损伤或心肌损伤后肺组织和心肌组织纤维化。我们发现阻断IL-17A也可以恢复博来霉素诱导的小鼠肺纤维化、胆总管结扎诱导的小鼠肝纤维化和腹主动脉缩窄诱导的小鼠心肌纤维化组织细胞中损伤的自噬活性。我们进一步使用上皮细胞研究发现,IL-17A能够直接阻断细胞自噬活性,并抑制自噬成分参与的胶原降解途径。而药理学阻断自噬活性能够逆转抗IL-17A中和性抗体对博来霉素诱导的小鼠肺纤维化的治疗作用。我们的结果提示,IL-17A可能通过诱导TGF-β1表达,促进肌成纤维细胞活化或直接抑制细胞自噬活性,参与多种组织纤维化的发生发展。IL-17A作为潜在的组织纤维化相关疾病治疗靶点,其研究具有重要的临床治疗和药物开发意义。
[Abstract]:Tissue remodeling disease has become one of the most serious public health problems worldwide. More than 45% of the world's annual deaths are due to various tissue remodeling diseases. Tissue fibrosis is a typical pathological change of tissue remodeling disease, and it is also the core pathological change of many kinds of chronic diseases. The mechanism of occurrence and development of tissue fibrosis is not very clear. It has been shown that many signaling pathways such as Smads and 尾-catenin are involved in the expression of tissue fibrosis related molecules. The activation of myofibroblasts is the basis of cell biology for the occurrence and development of tissue fibrosis. At the time of injury, many kinds of cells, such as TGF- 尾 _ 1 and IL-6, were transformed into myofibroblasts, activated, synthesized and released a lot of extracellular matrix such as collagen, and participated in the occurrence and development of tissue fibrosis. The nature of local immune microenvironment of chronic inflammation determines the nature of inflammation, and the nature of focal inflammation is the key to determine the prognosis of fibrosis related diseases. Studies have shown that the inhibitory immune microenvironment, dominated by Th2, exacerbates the occurrence and development of tissue fibrosis. However, Thl type immune microenvironment can improve the pathological condition of tissue fibrosis. Th17 cell is a newly identified T helper cell subtype independent of Th1/2. Its main effector, IL-17A, is thought to play an important role in many inflammatory and autoimmune diseases. We speculate that IL-17A is also involved in the development of tissue fibrosis. We first studied the relationship between IL-17A and tissue fibrosis at the animal and cell levels. The results showed that IL-17A could induce the secretion of TGF- 尾 1, promote the EMT reaction in epithelial cells, and induce the activation, synthesis and secretion of collagen in myofibroblasts. At the same time, the expression of IL-17A was significantly increased in bleomycin induced pulmonary fibrosis, common bile duct ligation induced liver fibrosis and abdominal aortic coarctation induced myocardial fibrosis in mice. Then, we used anti-IL-17A neutralizing antibodies to model mice with various fibrosis diseases. The results showed that blocking IL-17A could significantly improve pulmonary fibrosis induced by bleomycin or silica in mice. The hepatic fibrosis induced by common bile duct ligation and the myocardial fibrosis induced by abdominal aortic coarctation in mice were induced and the local inflammation of fibrosis tissue was improved. We have recently found that autophagy, as an effector of TLR4 activation, can promote the outcome of chronic inflammation and thus improve pulmonary and myocardial fibrosis after acute lung injury or myocardial injury. We found that blocking IL-17A could also restore the damaged autophagy activity in murine pulmonary fibrosis induced by bleomycin, hepatic fibrosis induced by common bile duct ligation and myocardial fibrosis induced by abdominal aortic coarctation. We found that IL-17A could directly block the autophagy activity and inhibit the collagen degradation pathway involved by autophagy. Pharmacological blockade of autophagy could reverse the effect of anti-IL-17A neutralizing antibody on bleomycin-induced pulmonary fibrosis in mice. Our results suggest that IL-17A may promote the activation or direct inhibition of autophagy activity of myofibroblasts by inducing TGF- 尾 1 expression. IL-17A may be used as a potential target for the treatment of fibrosis related diseases. Its research has important clinical treatment and drug development significance.
【学位授予单位】：北京协和医学院
【学位级别】：博士
【学位授予年份】：2012
【分类号】：R363

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