凋亡抑制蛋白c-FLIP(L)调控肺纤维化过程的机制研究
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南京大学生命科学学院

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江苏省自然科学基金面上项目(BK20161477)


The effect of c-FLIP(L) involved in the development of pulmonary fibrosis
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    摘要:

    目的:明确凋亡抑制蛋白c-FLIP(L)在肺纤维化过程中的作用,探究其异常表达参与肺纤维化发病的分子机制。方法:构建博来霉素诱导的小鼠肺纤维化模型,对正常鼠与模型鼠的肺组织切片进行HE和Masson染色观察病理变化,并采用免疫组化分析c-FLIP(L)及EMT标志分子E-cadherin的表达。构建c-FLIP(L)稳定细胞株,qRT-PCR检测EMT标志分子E-cadherin,N-cadherin及Vimentin的mRNA表达。采用TGF-β1诱导细胞发生EMT,通过Smad报告基因检测和western blot分析c-FLIP对TGF-β1诱导EMT发生的影响。结果: c-FLIP(L)表达水平在肺纤维化组织中明显升高,与E-cadherin表达呈负相关性。C-FLIP(L)能促进肺上皮细胞的EMT表型,并促进TGF-β1诱导的Smad信号通路激活,而敲减c-FLIP(L)表达能阻滞TGF-β1诱导的EMT进程。结论:c-FLIP(L)在肺纤维化过程中高表达能促进EMT发生,是肺纤维病程发展的促进因素之一。

    Abstract:

    Objective:To explore the effect of c-FLIP(L) in pulmonary fibrosis and its pathological mechanism. Methods: Based on bleomycin(BLM)induced idiopathic pulmonary fibrosis in mice, the expressions of c-FLIP and E-cadherin were analyzed by IHC staining. Further investigations in A549 cells overexpressing c-FLIP(L), the expression levels of E-cadherin, N-cadherin and Vimentin mRNA were examined by qRT-PCR, and Smad activation induced by TGF-β1 was detected by luciferase reporter assay and Western blot. Results: The increased c-FLIP expression was observed and associated with a decrease of E-cadherin expression. C-FLIP(L) overexpression resulted in the changes on E-cadherin, N-cadherin and Vimentin expressions in A549 cells. Furthemore, overexpression of c-FLIP(L) enhanced TGF-β-induced Smad activation, and knocking down c-FLIP(L) blocked the TGF-β1-induced EMT progress. Conclusion: C-FLIP(L) may be a promoting factor in the development of fibrosis via regulating EMT progress.

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  • 收稿日期:2021-01-12
  • 最后修改日期:2021-03-10
  • 录用日期:2021-09-28
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