Follistatin-like 1是肺纤维化的重要调节因子

发布时间：2021-08-21 19:04

　　特发性肺纤维化（IPF）是一种病因不明的,高度致死的慢性渐进性肺疾病,以成纤维细胞／肌纤维母细胞聚积和细胞外基质（ECM）过度沉积为特征。Fstl1是TGF-β1可诱导产生的分泌型胞外糖蛋白,最近发表的microarray数据表明Fstll在IPF患者的肺组织中表达量较正常人升高。在本研究中,我们发现Fstl1在IPF患者的肺组织和原代成纤维细胞中的表达量高于正常人。并且,Fstl1在博莱霉素所诱导的肺纤维化模型中也被诱导表达。因此,我们推测Fstl1在IPF病理过程中起到一定的作用。为了验证这一假设,Fstl1+/-和野生型小鼠经气管注射博莱霉素诱导形成肺纤维化。相对于野生型小鼠,Fstl1+/-小鼠具有正常的博莱霉素所引起的急性免疫反应。但是死亡曲线,组织学分析,羟脯氨酸测定以及免疫印迹分析都表明单倍缺失Fstl1明显抑制博莱霉素诱导形成的纤维化过程。ECM蛋白的过度沉积和重塑最终导致肺纤维化和肺泡功能的丧失。在肺组织和原代成纤维细胞中,单倍缺失Fstl1明显降低了博莱霉素所诱导的ECM蛋白的表达。另外,作为能够诱导ECM形成的TGF-β1在小鼠肺成纤维细胞中能够诱导Fstll的表... 

【文章来源】：南京大学江苏省 211工程院校 985工程院校 教育部直属院校

【文章页数】：98 页

【学位级别】：博士

【文章目录】：
Abstract
中文摘要
Abbreviations
Chapter1:Literature review of idiopathic pulmonary fibrosis
    1.1 Clinical description of IPF
    1.2 Pathogenesis of IPF
        1.2.1 IPF results from epithelial injury and abnormal wound healing
        1.2.2 Myofibroblasts in IPF
        1.2.3 Origin of myofibroblasts in IPF
        1.2.4 TGF-β1:a novel target for treatment of IPF
    1.3 Animal models of pulmonary fibrosis
    References
Chapter 2:Hyploinsufficiency of Fstl1 suppresses bleomycin-inducedpulmonary fibrosis
    1. Introduction
    2. Materials and methods
    3. Results
        Section Ⅰ. Altered expression of FSTL1 in IPF patients
            1.1 Microarray analysis of FSTL1 in IPF patients and controls
            1.2 FSTL1 expression in lung tissues of IPF patients and controls
            1.3 FSTL1 expression in PPFs from IPF patients and controls
            1.4 Fstl1 expression in lung tissues of mice after bleomycin treatment
            1.5 Fstl1 expression PPFs from mice after bleomycin treatment
            1.6 Localization of Fstl1 in lungs from mice after bleomycin treatment
            1.7 Conclusions
        Section Ⅱ.Fstl1~(+/-) mice have an attenuated fibrotic phenotype afterbleomycin-induced lung injury
            2.1 Expression of Fstll in Fstl1~(+/-) mice and WT controls after bleomycintreatment
            2.2 Survival curve of Fstl1~(+/-) mice and WT controls after bleomycin treatment
            2.3 Histological analysis of lung tissues from Fstl1~(+/-) mice and WT controls afterbleomycin treatment
            2.4 Collagen deposition of lung tissues from Fstl1~(+/-) mice and WT controls afterbleomycin treatment
            2.5 ECM deposition of lung tissues from Fstl1~(+/-) mice and WT controls afterbleomycin treatment
            2.6 Conclusions
        Section Ⅲ.Fstl1~(+/-) mice showed a normal acute response to bleomycin-inducedlung injury
            3.1 Total and differential inflammatory cells in BAL fluid
            3.2 Leukocyte and macrophage Subsets in whole lung tissues
            3.3 Th1/2 cytokines in BAL fluid and lung tissues
            3.4 Conclusions
        Section Ⅳ Fstl1~(+/-) mice exhibited reduced EMT process in response to bleomycin
            4.1 Decreased accumulation of myofibroblasts in Fstl1~(+/-) lungs afterbleomycin-induced injury
            4.2 Reduced EMT in Fstl1~(+/-) lungs during tissue injury
            4.3 Conclusions
        Section Ⅴ.Fstl1 exerts its pro-finbrotic role through modulating TGF-β signaling
            5.1 TGF-β1 induced Fstl1 expression in mouse lung fibroblasts and epithelial cells
            5.2 Fstl1 deletion suppresses TGF-β1-induced myofibroblasts activation and ECMproduction in lung fibroblasts
            5.3 Fstl1 promotes TGF-β1-induced EMT in vitro
            5.4 Fstl1 modulates TGF-β1-induced EMT via Smad signaling
            5.5 Fstl1 modulates TGF-β1-induced EMT via MAPK signaling
            5.6 Fstl1 binds to TGF-β1 in vitro
            5.7 Conclusions
    4. Conclusions and Discussions
    References
Acknowledgments
Publication



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