本文選題：白介素17A + 組織纖維化��； 參考：《北京協(xié)和醫(yī)學(xué)院》2012年博士論文

【摘要】：組織重構(gòu)性疾病已成為全球范圍內(nèi)最嚴(yán)重的公共衛(wèi)生問題之一。全球每年死亡人口中有超過45%是因?yàn)轭净几鞣N組織重構(gòu)性疾病。組織纖維化是組織重構(gòu)性疾病的典型病理改變,也是多種慢性疾病的核心病理改變,直接導(dǎo)致了慢性疾病的久治不愈遷延反復(fù)。組織纖維化的發(fā)生發(fā)展機(jī)制并不十分清楚�，F(xiàn)有研究表明,多種信號(hào)通路如Smads和β-catenin等參與介導(dǎo)組織纖維化相關(guān)分子表達(dá)。肌成纖維細(xì)胞活化是組織纖維化發(fā)生發(fā)展的細(xì)胞生物學(xué)基礎(chǔ)。損傷發(fā)生時(shí),多種細(xì)胞在不同刺激如TGF-β1、IL-6等下化生為肌成纖維細(xì)胞,活化并合成和釋放大量膠原等細(xì)胞外基質(zhì),參與組織纖維化發(fā)生發(fā)展。 慢性炎癥局部免疫微環(huán)境的性質(zhì)決定了炎癥的性質(zhì),而病灶局部炎癥的性質(zhì)是決定組織纖維化相關(guān)疾病預(yù)后的關(guān)鍵。研究表明,以Th2為主的抑制性免疫微環(huán)境加劇組織纖維化的發(fā)生發(fā)展,而Thl型免疫微環(huán)境卻能夠改善組織纖維化病理狀況。Th17型細(xì)胞是獨(dú)立于Th1/2的一種新近被鑒別出來的T輔助細(xì)胞亞型。其主要效應(yīng)因子IL-17A被認(rèn)為在多種炎癥相關(guān)疾病和自身免疫病中發(fā)揮重要作用。我們推測IL-17A也參與了組織纖維化的發(fā)生發(fā)展。 我們首先在動(dòng)物和細(xì)胞水平對(duì)IL-17A與組織纖維化的相關(guān)性進(jìn)行研究。研究結(jié)果表明,IL-17A能夠誘導(dǎo)促纖維化因子TGF-β1分泌,促進(jìn)上皮細(xì)胞發(fā)生EMT反應(yīng),誘導(dǎo)肌成纖維細(xì)胞活化,合成和分泌膠原。同時(shí),在博來霉素誘導(dǎo)的小鼠肺纖維化、膽總管結(jié)扎誘導(dǎo)的小鼠肝纖維化和腹主動(dòng)脈縮窄誘導(dǎo)的小鼠心肌纖維化組織中,IL-17A的表達(dá)水平顯著升高。接著,我們使用抗IL-17A中和性抗體對(duì)多種纖維化疾病模型小鼠進(jìn)行治療學(xué)研究。實(shí)驗(yàn)結(jié)果表明,阻斷IL-17A能夠顯著改善博來霉素或二氧化硅誘導(dǎo)的小鼠肺纖維化、膽總管結(jié)扎誘導(dǎo)的小鼠肝纖維化和腹主動(dòng)脈縮窄誘導(dǎo)的小鼠心肌纖維化并改善纖維化組織局部炎癥狀況,調(diào)節(jié)炎癥性質(zhì)向有利于纖維化消退的方向進(jìn)行。我們最近發(fā)現(xiàn)自噬作為TLR4活化的效應(yīng)機(jī)制,能夠促進(jìn)慢性炎癥轉(zhuǎn)歸進(jìn)而改善急性肺損傷或心肌損傷后肺組織和心肌組織纖維化。我們發(fā)現(xiàn)阻斷IL-17A也可以恢復(fù)博來霉素誘導(dǎo)的小鼠肺纖維化、膽總管結(jié)扎誘導(dǎo)的小鼠肝纖維化和腹主動(dòng)脈縮窄誘導(dǎo)的小鼠心肌纖維化組織細(xì)胞中損傷的自噬活性。我們進(jìn)一步使用上皮細(xì)胞研究發(fā)現(xiàn),IL-17A能夠直接阻斷細(xì)胞自噬活性,并抑制自噬成分參與的膠原降解途徑。而藥理學(xué)阻斷自噬活性能夠逆轉(zhuǎn)抗IL-17A中和性抗體對(duì)博來霉素誘導(dǎo)的小鼠肺纖維化的治療作用。 我們的結(jié)果提示,IL-17A可能通過誘導(dǎo)TGF-β1表達(dá),促進(jìn)肌成纖維細(xì)胞活化或直接抑制細(xì)胞自噬活性,參與多種組織纖維化的發(fā)生發(fā)展。IL-17A作為潛在的組織纖維化相關(guān)疾病治療靶點(diǎn),其研究具有重要的臨床治療和藥物開發(fā)意義。
[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.
【學(xué)位授予單位】：北京協(xié)和醫(yī)學(xué)院
【學(xué)位級(jí)別】：博士
【學(xué)位授予年份】：2012
【分類號(hào)】：R363

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本文編號(hào)：1799740