臺灣博碩士論文加值系統

特發性肺纖維化 (IPF) 是為原因不明之慢性且不可逆的肺部間質性肺病。組織病理學和肺部影像上可看見尋常性間質性肺炎之特徵。目前，特發性肺纖維化的藥物治療仍是有很大的進步空間。丙型干擾素 (IFN-γ) 在過去的許多研究中被報導可以減少纖維母細胞的增生與分化、調節免疫功能、及抑制膠原蛋白生成，以達到抗纖維化的效果。目前，丙型干擾素之臨床試驗結果被證實並無法有效改善病人死亡率，然而臨床試驗未成功的原因仍尚未被釐清。因此，本研究假設已分化之肺部肌纖維母細胞對丙型干擾素產生低反應性。在乙型轉化生長因子 (TGF-β1) 刺激之下，人類肺部纖維母細胞會分化成肌纖維母細胞 (myofibroblast)，並且伴隨著F-肌動蛋白 (F-actin)、平滑肌α肌動蛋白 (α-SMA)、纖網蛋白 (fibronectin)，及膠原蛋白的表現量增加。相較於肺部纖維母細胞，乙型轉化生長因子所誘發之肺部肌纖維母細胞對於丙型干擾素刺激所磷酸化的STAT-1與IP-10有較低的表現量。同時微列陣分析結果亦顯示，肺部肌纖維母細胞中大多數之丙型干擾素相關基因被抑制。此外，在對丙型干擾素產生低反應性之肺部肌纖維母細胞中，Src homology-2 domain-containing phosphatase 2 (SHP2) 及suppressors of cytokine signaling (SOCSs) 的表現比肺部纖維母細胞高。SHP2的活化來自活性氧物質 (ROS) 的產生，並且透過AKT/肝醣合成酶激酶-3β的激活路徑，而SOCS3的高表現則是來自於介白素-6所轉導STAT3的活化。此外，目前IPF現行用藥尼達尼布 (Nintedanib) 處理會抑制SHP2的活化與SOCS3的表現。合併丙型干擾素及尼達尼布治療，則顯示有減少肌纖維母細胞中的平滑肌α肌動蛋白表現的協同效果。進一步在博萊黴素 (bleomycin) 誘導的大鼠肺纖維化模式中，亦可發現SHP2的磷酸化、STAT3的磷酸化增加、以及SOCS3的蛋白表現量增加，並且與肺間質病變及膠原蛋白沉積有高度相關性。因此，我們推論ROS/AKT/GSK-3β/SHP2軸及IL-6/STAT3/SOCS3軸之訊息傳遞，有效促使肺纖維化之肌纖維母細胞產生丙型干擾素低反應性，而合併藥物處理以增強丙型干擾素之免疫監控能力，仍然是為潛在的抗纖維化治療策略。

Idiopathic pulmonary fibrosis (IPF) is a chronic, irreversible and lethal phenotype of unknown etiology with the histopathologic and/or radiologic pattern of usual interstitial pneumonia. So far, the efficacious therapy of IPF is still limited. Interferon (IFN)-γ confers anti-fibrosis by inhibiting fibroblast proliferation and collagen generation. However, a clinical trial of IFN-γ-based anti-fibrotic therapy fails by unknown events. We hypothesized that differentiated myofibroblasts were highly insensitive to IFN-γ immune-surveillance. Treatment of transforming growth factor-β1 (TGF-β1) caused human pulmonary fibroblasts differentiation toward myofibroblasts characterized with the increased bundles of F-actin, enhanced expression of α-smooth muscle actin (α-SMA), fibronectin and collagen. While microarray showed a decrease in IFN-γ-associated genes in myofibroblasts, IFN-γ-induced phosphorylation of signal transducer and activator of transcription 1 (STAT1) and the expression of IFN-γ-inducible protein 10 (IP-10) were significantly suppressed. In IFN-γ hypo-responsive myofibroblasts, Src homology-2 domain-containing phosphatase 2 (SHP2) and the suppressors of cytokine signaling (SOCSs) were upregulated. An AKT-regulated glycogen synthase kinase (GSK)-3β/SHP2 axis was induced in reactive oxygen species (ROS)-dependent manner, while autocrine secretion of interleukin-6 (IL-6) transduced STAT3-mediated SOCS3 induction. Treatment nintedanib (bibf1120), the Food and Drug Administration (FDA) approval drug for IPF, in myofibroblasts exerted effective inhibitions on either SHP2 or SOCS3. Synergistically treating myofibroblasts with Nintedanib and IFN-γ showed a marked suppression of α-SMA. Expression of phospho-SHP2, phospho-STAT3 and SOCS3 were validated in bleomycin-induced rat pulmonary fibrosis highly association with pulmonary parenchymal lesions and collagen deposition in vivo. Accordingly, we speculate that both ROS/AKT/GSK-3β/SHP2 and IL-6/STAT3/SOCS3 axis signaling pathways cause IFN-γ hypo-responsiveness in TGF-β-stimulated myofibroblasts, while reversing IFN-γ immune-surveillance remains serving the potential anti-fibrosis therapeutic efficacy.

中文摘要 I
Abstract II
Acknowledgement III
Contents V
Figure lists VIII
Abbreviations IX
I. Introduction 1
I-1. Idiopathic pulmonary fibrosis (IPF) 2
I-2. Clinical presentation of IPF 2
I-3. Epidemiology of IPF 3
I-4. Pharmacologic management of IPF 3
I-5. Pathobiology of IPF 5
I-6. TGF-β1 activation 5
I-7. Fibroblast-myofibroblast transition (FMT) 6
I-8. IFN-γ in IPF 7
II. Objective and Specific Aims 10
III. Materials and Methods 12
III-1. Materials 13
III-2. Methods 16
IV. Results 21
IV-1. TGF-β1 induces fibroblast-myofibroblast transition. 22
IV-2. TGF-β1-differentiated myofibroblasts present hypo-responsiveness to IFN-γ stimulation. 23
IV-3. Aberrant activation of SHP2, SOCS1, SOCS3, and PIAS1 in myofibroblasts determines IFN-γ hypo-responsiveness. 23
IV-4. ROS-mediated AKT/GSK-3β axis regulates SHP2 activation in TGF-β1-differentiated myofibroblasts. 24
IV-5. IL-6 signaling mediates SOCS3 upregulation in TGF-β1-differentiated myofibroblasts. 25
IV-6. Bibf1120 inhibits SHP2 activation and SOCS3 expression. 25
IV-7. The activation of SHP2 and SOCS3 in bleomycin-induced pulmonary fibrosis. 26
V. Discussion 28
V-1. TGF-β1 induces fibroblast-myofibroblast transition (FMT) in pulmonary fibrosis 29
V-2. The effects of IFN-γ on pulmonary fibrosis 29
V-3. SHP2 hyper-activation in pulmonary fibrosis 30
V-4. SOCS3 in pulmonary fibrosis 31
V-5. The inhibition of SHP2 and SOCS3 against pulmonary fibrosis 32
V-6. Bleomycin-induced pulmonary fibrosis in vivo 33
V-7. Applications and limitations of our study 34
VI. Conclusion 36
VII. References 38
VIII. Figures and Figure legends 48
Figure 1. TGF-β1 induces fibroblast-myofibroblast transition. 49
Figure 2. TGF-β1-differentiated myofibroblasts are hypo-responsiveness to IFN-γ stimulation. 51
Figure 3. IFN-γ-response genes and IP-10 expression are reduced in TGF-β1-differentiated myofibroblasts. 52
Figure 4. Upregulation of SHP2, SOCS1, SOCS3, and PIAS1 in TGF-β1-differentiated myofibroblasts. 53
Figure 5. The ROS generation initiates AKT/GSK-3β/SHP2 axis activation in TGF-β1-differentiated myofibroblasts. 54
Figure 6. IL-6 induces STAT3-dependent SOCS3 expression in TGF-β1-differentiated myofibroblasts. 55
Figure 7. Bibf1120 inhibits SHP2 and SOCS3 expression. 56
Figure 8. Combination of bibf1120 and IFN-γ treatment reduces α-SMA expression than the monotherapy in TGF-β1-differentiated myofibroblasts. 57
Figure 9. The activation of SHP2, STAT3, and SOCS3 in bleomycin-mediated fibrotic lung tissues. 58
Figure 10. A schematic model of this study. 60
IX. Appendix 61
IX-1. Figure 62
IX-2. Materials and Methods 63

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