特發(fā)性肺纖維化（IPF）是一種病因不明的,高度致死的慢性漸進性肺疾病,以成纖維細胞／肌纖維母細胞聚積和細胞外基質(zhì)（ECM）過度沉積為特征。Fstl1是TGF-β1可誘導產(chǎn)生的分泌型胞外糖蛋白,最近發(fā)表的microarray數(shù)據(jù)表明Fstll在IPF患者的肺組織中表達量較正常人升高。在本研究中,我們發(fā)現(xiàn)Fstl1在IPF患者的肺組織和原代成纖維細胞中的表達量高于正常人。并且,Fstl1在博萊霉素所誘導的肺纖維化模型中也被誘導表達。因此,我們推測Fstl1在IPF病理過程中起到一定的作用。為了驗證這一假設,Fstl1+/-和野生型小鼠經(jīng)氣管注射博萊霉素誘導形成肺纖維化。相對于野生型小鼠,Fstl1+/-小鼠具有正常的博萊霉素所引起的急性免疫反應。但是死亡曲線,組織學分析,羥脯氨酸測定以及免疫印跡分析都表明單倍缺失Fstl1明顯抑制博萊霉素誘導形成的纖維化過程。ECM蛋白的過度沉積和重塑最終導致肺纖維化和肺泡功能的喪失。在肺組織和原代成纖維細胞中,單倍缺失Fstl1明顯降低了博萊霉素所誘導的ECM蛋白的表達。另外,作為能夠誘導ECM形成的TGF-β1在小鼠肺成纖維細胞中能夠誘導Fstll的表... 

【文章來源】：南京大學江蘇省 211工程院校 985工程院校 教育部直屬院校

【文章頁數(shù)】：98 頁

【學位級別】：博士

【文章目錄】：
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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