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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20480完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 楊鎧鍵(Kai-Chien Yang) | |
| dc.contributor.author | Ying Tung Lee | en |
| dc.contributor.author | 李尹彤 | zh_TW |
| dc.date.accessioned | 2021-06-08T02:50:10Z | - |
| dc.date.copyright | 2017-09-13 | |
| dc.date.issued | 2017 | |
| dc.date.submitted | 2017-08-16 | |
| dc.identifier.citation | 1. About PF. Available from: http://www.pulmonaryfibrosis.org/life-with-pf/about-pf.
2. Clark, R.A., Basics of cutaneous wound repair. J Dermatol Surg Oncol, 1993. 19(8): p. 693-706. 3. JM., D., Wound repair, in Raven Press. 1992: New York, NY. 4. Keane MP, B.J., Henson PM, et al., Inflammation, injury, and repair. 4th ed. Textbook of respiratory medicine. 2005, Philadelphia, PA: Elsevier Saunders. 5. Wallace, W.A., et al., Inflammation-associated remodelling and fibrosis in the lung - a process and an end point. Int J Exp Pathol, 2007. 88(2): p. 103-10. 6. Basset, F., et al., Intraluminal fibrosis in interstitial lung disorders. Am J Pathol, 1986. 122(3): p. 443-61. 7. Corrin, B., et al., Fine structural changes in cryptogenic fibrosing alveolitis and asbestosis. J Pathol, 1985. 147(2): p. 107-19. 8. Kuhn, C., 3rd, et al., An immunohistochemical study of architectural remodeling and connective tissue synthesis in pulmonary fibrosis. Am Rev Respir Dis, 1989. 140(6): p. 1693-703. 9. McDonald, J.A., Idiopathic pulmonary fibrosis. A paradigm for lung injury and repair. Chest, 1991. 99(3 Suppl): p. 87S-93S. 10. Strieter, R.M., B.N. Gomperts, and M.P. Keane, The role of CXC chemokines in pulmonary fibrosis. J Clin Invest, 2007. 117(3): p. 549-56. 11. Strieter, R.M., Pathogenesis and natural history of usual interstitial pneumonia: the whole story or the last chapter of a long novel. Chest, 2005. 128(5 Suppl 1): p. 526S-532S. 12. Chambers, R.C., Role of coagulation cascade proteases in lung repair and fibrosis. Eur Respir J Suppl, 2003. 44: p. 33s-35s. 13. Dik, W.A., et al., Thrombin contributes to bronchoalveolar lavage fluid mitogenicity in lung disease of the premature infant. Pediatr Pulmonol, 2003. 35(1): p. 34-41. 14. Hernandez-Rodriguez, N.A., et al., Role of thrombin in pulmonary fibrosis. Lancet, 1995. 346(8982): p. 1071-3. 15. Gabazza, E.C., et al., Thrombin in the airways of asthmatic patients. Lung, 1999. 177(4): p. 253-62. 16. Chen, L.B. and J.M. Buchanan, Mitogenic activity of blood components. I. Thrombin and prothrombin. Proc Natl Acad Sci U S A, 1975. 72(1): p. 131-5. 17. Bogatkevich, G.S., et al., Thrombin differentiates normal lung fibroblasts to a myofibroblast phenotype via the proteolytically activated receptor-1 and a protein kinase C-dependent pathway. J Biol Chem, 2001. 276(48): p. 45184-92. 18. Chambers, R.C., et al., Thrombin stimulates fibroblast procollagen production via proteolytic activation of protease-activated receptor 1. Biochem J, 1998. 333 ( Pt 1): p. 121-7. 19. McKeown, S., et al., MMP expression and abnormal lung permeability are important determinants of outcome in IPF. Eur Respir J, 2009. 33(1): p. 77-84. 20. Ruiz, V., et al., Unbalanced collagenases/TIMP-1 expression and epithelial apoptosis in experimental lung fibrosis. Am J Physiol Lung Cell Mol Physiol, 2003. 285(5): p. L1026-36. 21. Gadek, J.E., et al., Collagenase in the lower respiratory tract of patients with idiopathic pulmonary fibrosis. N Engl J Med, 1979. 301(14): p. 737-42. 22. O'Connor, C., et al., Collagenase and fibronectin in bronchoalveolar lavage fluid in patients with sarcoidosis. Thorax, 1988. 43(5): p. 393-400. 23. Oggionni, T., et al., Time course of matrix metalloproteases and tissue inhibitors in bleomycin-induced pulmonary fibrosis. Eur J Histochem, 2006. 50(4): p. 317-25. 24. O'Connor, C.M. and M.X. FitzGerald, Matrix metalloproteases and lung disease. Thorax, 1994. 49(6): p. 602-9. 25. Pardo, A. and M. Selman, Matrix metalloproteases in aberrant fibrotic tissue remodeling. Proc Am Thorac Soc, 2006. 3(4): p. 383-8. 26. Elovic, A.E., et al., IL-4-dependent regulation of TGF-alpha and TGF-beta1 expression in human eosinophils. J Immunol, 1998. 160(12): p. 6121-7. 27. Minshall, E.M., et al., Eosinophil-associated TGF-beta1 mRNA expression and airways fibrosis in bronchial asthma. Am J Respir Cell Mol Biol, 1997. 17(3): p. 326-33. 28. Ohno, I., et al., Transforming growth factor beta 1 (TGF beta 1) gene expression by eosinophils in asthmatic airway inflammation. Am J Respir Cell Mol Biol, 1996. 15(3): p. 404-9. 29. Wenzel, S.E., et al., TGF-beta and IL-13 synergistically increase eotaxin-1 production in human airway fibroblasts. J Immunol, 2002. 169(8): p. 4613-9. 30. Zagai, U., et al., Eosinophil cationic protein stimulates TGF-beta1 release by human lung fibroblasts in vitro. Inflammation, 2007. 30(5): p. 153-60. 31. Fertin, C., et al., Interleukin-4 stimulates collagen synthesis by normal and scleroderma fibroblasts in dermal equivalents. Cell Mol Biol, 1991. 37(8): p. 823-9. 32. Sempowski, G.D., et al., Subsets of murine lung fibroblasts express membrane-bound and soluble IL-4 receptors. Role of IL-4 in enhancing fibroblast proliferation and collagen synthesis. J Immunol, 1994. 152(7): p. 3606-14. 33. Strutz, F., et al., TGF-beta 1 induces proliferation in human renal fibroblasts via induction of basic fibroblast growth factor (FGF-2). Kidney Int, 2001. 59(2): p. 579-92. 34. Wynn, T.A., IL-13 effector functions. Annu Rev Immunol, 2003. 21: p. 425-56. 35. Wynn, T.A., Fibrotic disease and the T(H)1/T(H)2 paradigm. Nat Rev Immunol, 2004. 4(8): p. 583-94. 36. Driscoll, K.E., et al., Stimulation of rat alveolar macrophage fibronectin release in a cadmium chloride model of lung injury and fibrosis. Toxicol Appl Pharmacol, 1992. 116(1): p. 30-7. 37. Kadler, K.E., A. Hill, and E.G. Canty-Laird, Collagen fibrillogenesis: fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol, 2008. 20(5): p. 495-501. 38. Iwano, M., et al., Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest, 2002. 110(3): p. 341-50. 39. Venkatesan, N., P.J. Roughley, and M.S. Ludwig, Proteoglycan expression in bleomycin lung fibroblasts: role of transforming growth factor-beta(1) and interferon-gamma. Am J Physiol Lung Cell Mol Physiol, 2002. 283(4): p. L806-14. 40. Bensadoun, E.S., et al., Proteoglycan deposition in pulmonary fibrosis. Am J Respir Crit Care Med, 1996. 154(6 Pt 1): p. 1819-28. 41. McGowan, S.E., Extracellular matrix and the regulation of lung development and repair. FASEB J, 1992. 6(11): p. 2895-904. 42. Parra, E.R., et al., Abnormal deposition of collagen/elastic vascular fibres and prognostic significance in idiopathic interstitial pneumonias. Thorax, 2007. 62(5): p. 428-37. 43. Singer, II, Fibronexus formation is an early event during fibronectin-induced restoration of more normal morphology and substrate adhesion patterns in transformed hamster fibroblasts. J Cell Sci, 1982. 56: p. 1-20. 44. Garcia-Alvarez, J., et al., Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis. Exp Lung Res, 2006. 32(5): p. 201-14. 45. Gill, S.E. and W.C. Parks, Metalloproteinases and their inhibitors: regulators of wound healing. Int J Biochem Cell Biol, 2008. 40(6-7): p. 1334-47. 46. Fattman, C.L., Apoptosis in pulmonary fibrosis: too much or not enough? Antioxid Redox Signal, 2008. 10(2): p. 379-85. 47. Moodley, Y.P., et al., Comparison of the morphological and biochemical changes in normal human lung fibroblasts and fibroblasts derived from lungs of patients with idiopathic pulmonary fibrosis during FasL-induced apoptosis. J Pathol, 2004. 202(4): p. 486-95. 48. Buhling, F., et al., Altered expression of membrane-bound and soluble CD95/Fas contributes to the resistance of fibrotic lung fibroblasts to FasL induced apoptosis. Respir Res, 2005. 6: p. 37. 49. Maeyama, T., et al., Upregulation of Fas-signalling molecules in lung epithelial cells from patients with idiopathic pulmonary fibrosis. Eur Respir J, 2001. 17(2): p. 180-9. 50. Korfei, M., et al., Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2008. 178(8): p. 838-46. 51. Strieter, R.M. and B. Mehrad, New mechanisms of pulmonary fibrosis. Chest, 2009. 136(5): p. 1364-1370. 52. Ley, B. and H.R. Collard, Epidemiology of idiopathic pulmonary fibrosis. Clin Epidemiol, 2013. 5: p. 483-92. 53. Lai, C.C., et al., Idiopathic pulmonary fibrosis in Taiwan - a population-based study. Respir Med, 2012. 106(11): p. 1566-74. 54. Xu, C., B. Bailly-Maitre, and J.C. Reed, Endoplasmic reticulum stress: cell life and death decisions. J Clin Invest, 2005. 115(10): p. 2656-64. 55. Kober, L., C. Zehe, and J. Bode, Development of a novel ER stress based selection system for the isolation of highly productive clones. Biotechnol Bioeng, 2012. 109(10): p. 2599-611. 56. Back, S.H., et al., Cytoplasmic IRE1alpha-mediated XBP1 mRNA splicing in the absence of nuclear processing and endoplasmic reticulum stress. J Biol Chem, 2006. 281(27): p. 18691-706. 57. Schroder, M. and R.J. Kaufman, The mammalian unfolded protein response. Annu Rev Biochem, 2005. 74: p. 739-89. 58. Song, B., et al., Chop deletion reduces oxidative stress, improves beta cell function, and promotes cell survival in multiple mouse models of diabetes. J Clin Invest, 2008. 118(10): p. 3378-89. 59. Qiu, Y., et al., A crucial role for RACK1 in the regulation of glucose-stimulated IRE1alpha activation in pancreatic beta cells. Sci Signal, 2010. 3(106): p. ra7. 60. Bettigole, S.E., et al., The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol, 2015. 16(8): p. 829-37. 61. Korennykh, A.V., et al., The unfolded protein response signals through high-order assembly of Ire1. Nature, 2009. 457(7230): p. 687-93. 62. Bertolotti, A., et al., Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol, 2000. 2(6): p. 326-32. 63. Tanjore, H., W.E. Lawson, and T.S. Blackwell, Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta, 2013. 1832(7): p. 940-7. 64. Grootjans, J., et al., The unfolded protein response in immunity and inflammation. Nat Rev Immunol, 2016. 16(8): p. 469-84. 65. Wang, M. and R.J. Kaufman, Protein misfolding in the endoplasmic reticulum as a conduit to human disease. Nature, 2016. 529(7586): p. 326-35. 66. Harding, H.P., Y. Zhang, and D. Ron, Protein translation and folding are coupled by an endoplasmic-reticulum-resident kinase. Nature, 1999. 397(6716): p. 271-4. 67. Tashiro, E., et al., Trierixin, a novel Inhibitor of ER stress-induced XBP1 activation from Streptomyces sp. 1. Taxonomy, fermentation, isolation and biological activities. J Antibiot (Tokyo), 2007. 60(9): p. 547-53. 68. Zhang, L., et al., Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis. Am J Transl Res, 2017. 9(2): p. 722-735. 69. Plataki, M., et al., Expression of apoptotic and antiapoptotic markers in epithelial cells in idiopathic pulmonary fibrosis. Chest, 2005. 127(1): p. 266-74. 70. Gunther, A., et al., Prevention of bleomycin-induced lung fibrosis by aerosolization of heparin or urokinase in rabbits. Am J Respir Crit Care Med, 2003. 168(11): p. 1358-65. 71. Kuwano, K., Involvement of epithelial cell apoptosis in interstitial lung diseases. Intern Med, 2008. 47(5): p. 345-53. 72. Cheresh, P., et al., Oxidative stress and pulmonary fibrosis. Biochim Biophys Acta, 2013. 1832(7): p. 1028-40. 73. Cui, Y., et al., Oxidative stress contributes to the induction and persistence of TGF-beta1 induced pulmonary fibrosis. Int J Biochem Cell Biol, 2011. 43(8): p. 1122-33. 74. Lekkerkerker, A.N., et al., Cellular players in lung fibrosis. Curr Pharm Des, 2012. 18(27): p. 4093-102. 75. Mo, X.T., et al., Inositol-requiring protein 1 - X-box-binding protein 1 pathway promotes epithelial-mesenchymal transition via mediating snail expression in pulmonary fibrosis. Int J Biochem Cell Biol, 2015. 65: p. 230-8. 76. Tao, B., et al., Myeloid-specific disruption of tyrosine phosphatase Shp2 promotes alternative activation of macrophages and predisposes mice to pulmonary fibrosis. J Immunol, 2014. 193(6): p. 2801-11. 77. Gharib, S.A., et al., MMP28 promotes macrophage polarization toward M2 cells and augments pulmonary fibrosis. J Leukoc Biol, 2014. 95(1): p. 9-18. 78. Wynn, T.A., A. Chawla, and J.W. Pollard, Macrophage biology in development, homeostasis and disease. Nature, 2013. 496(7446): p. 445-55. 79. Oh, J., et al., Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem, 2012. 287(15): p. 11629-41. 80. Marcus, N., et al., Tissue distribution of three members of the murine protein disulfide isomerase (PDI) family. Biochim Biophys Acta, 1996. 1309(3): p. 253-60. 81. Noiva, R., Protein disulfide isomerase: the multifunctional redox chaperone of the endoplasmic reticulum. Semin Cell Dev Biol, 1999. 10(5): p. 481-93. 82. Edman, J.C., et al., Sequence of protein disulphide isomerase and implications of its relationship to thioredoxin. Nature, 1985. 317(6034): p. 267-70. 83. Koch, G.L., Reticuloplasmins: a novel group of proteins in the endoplasmic reticulum. J Cell Sci, 1987. 87 ( Pt 4): p. 491-2. 84. Yoshimori, T., et al., Protein disulfide-isomerase in rat exocrine pancreatic cells is exported from the endoplasmic reticulum despite possessing the retention signal. J Biol Chem, 1990. 265(26): p. 15984-90. 85. Ali Khan, H. and B. Mutus, Protein disulfide isomerase a multifunctional protein with multiple physiological roles. Front Chem, 2014. 2: p. 70. 86. Wilkinson, B. and H.F. Gilbert, Protein disulfide isomerase. Biochim Biophys Acta, 2004. 1699(1-2): p. 35-44. 87. Gruber, C.W., et al., Protein disulfide isomerase: the structure of oxidative folding. Trends Biochem Sci, 2006. 31(8): p. 455-64. 88. Galligan, J.J. and D.R. Petersen, The human protein disulfide isomerase gene family. Hum Genomics, 2012. 6: p. 6. 89. Morand, J.P., J. Macri, and K. Adeli, Proteomic profiling of hepatic endoplasmic reticulum-associated proteins in an animal model of insulin resistance and metabolic dyslipidemia. J Biol Chem, 2005. 280(18): p. 17626-33. 90. Sullivan, D.C., et al., EndoPDI, a novel protein-disulfide isomerase-like protein that is preferentially expressed in endothelial cells acts as a stress survival factor. J Biol Chem, 2003. 278(47): p. 47079-88. 91. Horna-Terron, E., et al., TXNDC5, a newly discovered disulfide isomerase with a key role in cell physiology and pathology. Int J Mol Sci, 2014. 15(12): p. 23501-18. 92. Gulerez, I.E., et al., Structure of the third catalytic domain of the protein disulfide isomerase ERp46. Acta Crystallogr Sect F Struct Biol Cryst Commun, 2012. 68(Pt 4): p. 378-81. 93. Knoblach, B., et al., ERp19 and ERp46, new members of the thioredoxin family of endoplasmic reticulum proteins. Mol Cell Proteomics, 2003. 2(10): p. 1104-19. 94. Kojima, R., et al., Radically different thioredoxin domain arrangement of ERp46, an efficient disulfide bond introducer of the mammalian PDI family. Structure, 2014. 22(3): p. 431-43. 95. Karolchik, D., et al., The UCSC Genome Browser database: 2014 update. Nucleic Acids Res, 2014. 42(Database issue): p. D764-70. 96. Kent, W.J., et al., The human genome browser at UCSC. Genome Res, 2002. 12(6): p. 996-1006. 97. Helms, M.N., et al., Direct tracheal instillation of solutes into mouse lung. J Vis Exp, 2010(42). 98. Hinz, B., et al., The myofibroblast: one function, multiple origins. Am J Pathol, 2007. 170(6): p. 1807-16. 99. Lenna, S. and M. Trojanowska, The role of endoplasmic reticulum stress and the unfolded protein response in fibrosis. Curr Opin Rheumatol, 2012. 24(6): p. 663-8. 100. Lee, J.C., et al., A protein kinase involved in the regulation of inflammatory cytokine biosynthesis. Nature, 1994. 372(6508): p. 739-46. 101. Guan, Z., et al., Induction of cyclooxygenase-2 by the activated MEKK1 --> SEK1/MKK4 --> p38 mitogen-activated protein kinase pathway. J Biol Chem, 1998. 273(21): p. 12901-8. 102. Zarubin, T. and J. Han, Activation and signaling of the p38 MAP kinase pathway. Cell Res, 2005. 15(1): p. 11-8. 103. He, C.H., et al., Bcl-2-related protein A1 is an endogenous and cytokine-stimulated mediator of cytoprotection in hyperoxic acute lung injury. J Clin Invest, 2005. 115(4): p. 1039-48. 104. Leonard, W.J., Role of Jak kinases and STATs in cytokine signal transduction. Int J Hematol, 2001. 73(3): p. 271-7. 105. Hokuto, I., et al., Stat-3 is required for pulmonary homeostasis during hyperoxia. J Clin Invest, 2004. 113(1): p. 28-37. 106. Leonard, W.J. and J.J. O'Shea, Jaks and STATs: biological implications. Annu Rev Immunol, 1998. 16: p. 293-322. 107. Bromberg, J., Signal transducers and activators of transcription as regulators of growth, apoptosis and breast development. Breast Cancer Res, 2000. 2(2): p. 86-90. 108. Bromberg, J. and X. Chen, STAT proteins: signal tranducers and activators of transcription. Methods Enzymol, 2001. 333: p. 138-51. 109. Bromberg, J. and J.E. Darnell, Jr., The role of STATs in transcriptional control and their impact on cellular function. Oncogene, 2000. 19(21): p. 2468-73. 110. Fu, X.Y., STAT3 in immune responses and inflammatory bowel diseases. Cell Res, 2006. 16(2): p. 214-9. 111. Wu, S.H., et al., Lipoxin A4 inhibits proliferation of human lung fibroblasts induced by connective tissue growth factor. Am J Respir Cell Mol Biol, 2006. 34(1): p. 65-72. 112. Brar, G.A. and J.S. Weissman, Ribosome profiling reveals the what, when, where and how of protein synthesis. Nat Rev Mol Cell Biol, 2015. 16(11): p. 651-64. 113. Raghu, G., et al., A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis. N Engl J Med, 2004. 350(2): p. 125-33. 114. Raghu, G., et al., An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011. 183(6): p. 788-824. 115. Raghu, G., et al., An Official ATS/ERS/JRS/ALAT Clinical Practice Guideline: Treatment of Idiopathic Pulmonary Fibrosis. An Update of the 2011 Clinical Practice Guideline. Am J Respir Crit Care Med, 2015. 192(2): p. e3-19. 116. Carlos, W.G., et al., Treatment of Idiopathic Pulmonary Fibrosis. Ann Am Thorac Soc, 2016. 13(1): p. 115-7. 117. Richeldi, L., et al., Efficacy and safety of nintedanib in idiopathic pulmonary fibrosis. N Engl J Med, 2014. 370(22): p. 2071-82. 118. King, T.E., Jr., et al., A phase 3 trial of pirfenidone in patients with idiopathic pulmonary fibrosis. N Engl J Med, 2014. 370(22): p. 2083-92. 119. Rockey, D.C., P.D. Bell, and J.A. Hill, Fibrosis--a common pathway to organ injury and failure. N Engl J Med, 2015. 372(12): p. 1138-49. 120. Pardo, A., et al., Up-regulation and profibrotic role of osteopontin in human idiopathic pulmonary fibrosis. PLoS Med, 2005. 2(9): p. e251. 121. Selman, M., et al., Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches. Drugs, 2004. 64(4): p. 405-30. 122. Selman, M. and A. Pardo, Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc, 2006. 3(4): p. 364-72. 123. Willis, B.C., et al., Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-beta1: potential role in idiopathic pulmonary fibrosis. Am J Pathol, 2005. 166(5): p. 1321-32. | |
| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/20480 | - |
| dc.description.abstract | 肺纖維化 (pulmonary fibrosis) 是肺組纖產生嚴重結痂變化，可以是原發性或次發於其他肺部或系統性疾病。肺纖維化的形成，始於肺組織中的纖維母細胞 (fibroblast) 因受到各種化學性或物理性刺激時，被活化而增生，並持續分泌細胞外間質(extracellular matrix)如膠原蛋白 (Collagen)，纖維化的過程會扭曲肺的結構，並導致肺泡壁組織增厚，造成不可逆的肺組織氧氣交換的能力喪失、低氧血症 (hypoxemia)，呼吸困難，運動不耐，甚至會造成死亡。肺纖維化疾病，尤其是特發性肺纖維化，是在臨床疾病中預後最差的疾病之一，然而目前對於肺纖維化的治療是非常有限的。在肺部結痂以後，恢復原狀很困難，唯一的治療方法是肺臟移植手術，然而只有極少數的患者能獲得移植治療。因此，目前亟需探尋新的肺纖維化分子機轉，以發展新型的肺纖維化治療方法或藥物。透過生物資訊學分析、細胞以及動物實驗，我們發現內質網蛋白 TXNDC5 (Thioredoxin domain containing 5，硫氧還蛋白5) 在肺纖維化中扮演重要的角色。在人類與小鼠肺纖維化組織與正常肺組織相較之下，TXNDC5在肺纖維化組織中的mRNA或蛋白質表現量都高度上升，其表現量也與促進肺纖維化形成的基因或蛋白質有高度相關性。人類以及老鼠的纖維母細胞在接受促進纖維化因子，轉化生長因子-β (transforming growth factor beta, TGF-β1) 刺激時，TXNDC5 的表現量會明顯增加。當TXNDC5的基因被降解 (knockdown) 後，TGF-β1刺激引起的纖維化相關蛋白質包括膠原蛋白以及 elastin 的蛋白質表現量被降低，同時也抑制了纖維母細胞受TGF-β1刺激活化為肌成纖維細胞及細胞增生的作用。在小鼠動物模型中，我們也發現TXNDC5-/-小鼠會減少因化療藥(bleomycin) 導致的肺纖維化，呼吸速率增加以及肺結構扭曲。從上述的結果，我們可以得知TXNDC5在肺纖維化扮演著重要的角色。未來將會針對TXNDC5發展出新型的肺纖維化治療藥物。 | zh_TW |
| dc.description.abstract | Pulmonary fibrosis (PF), a condition of excessive scarring in the lung tissue, can be idiopathic or secondary to various medical conditions. PF can lead to distorted pulmonary architecture, impaired lung function and alveolar gas exchange, resulting in hypoxemia, dyspnea, exercise intolerance and even death. Owing to the grave outcomes and tremendous health care burden associated with PF, it has become a major and growing public health problem. In spite of the advances in medicine, the incidence and mortality rate of PF remain high and options for PF therapeutics are very limited. There is a clear need to identify novel mediators and pathways of lung fibrosis to develop therapies to improve the outcomes of PF patients. Through a combined bioinformatic and experimental approach, we have recently identified an endoplasmic reticulum (ER)-resident protein thioredoxin domain containing 5 (TXNDC5) as a pivotal mediator of lung fibrosis. The mRNA and protein expression levels of TXNDC5 are highly up-regulated and positively correlate with that of extracellular matrix (ECM) proteins in lung tissues from patients with idiopathic pulmonary fibrosis (IPF) and in a mouse model of bleomycin-induced PF. In human and mouse lung fibroblasts, TXNDC5 is markedly up-regulated in response to profibrotic cytokine TGFβ1 stimulation. Knocking down TXNDC5 in lung fibroblasts leads to down-regulation of ECM proteins including collagen and elastin, as well as the inhibition of fibroblast activation/myofibroblast transformation in response to TGFβ treatment. Importantly, TXNDC5 knockout mice appear to show resistance against lung volume reduction and pulmonary fibrosis induced by bleomycin treatment. Taken together, our data suggest a critical role of TXNDC5 in the pathogenesis of pulmonary fibrosis. Targeting TXNDC5, therefore, could be a potential novel therapeutic approach to treat PF. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T02:50:10Z (GMT). No. of bitstreams: 1 ntu-106-R04443021-1.pdf: 4277617 bytes, checksum: 41a88e946fe948bdfcc9afb926b50a1e (MD5) Previous issue date: 2017 | en |
| dc.description.tableofcontents | Table of Contents
致謝 III 中文摘要 V Abstract VII Table of Contents IX List of Figures XI List of Tables XII List of Abbreviations XIII CHAPTER 1. Introduction 1 1.1. Pulmonary fibrosis 1 1.1.1. Diseases leading to pulmonary fibrosis 1 1.1.2. Mechanism of pulmonary fibrosis 2 1.1.3. Idiopathic Pulmonary Fibrosis (IPF) 5 1.2. Endoplasmic reticulum(ER) stress 6 1.3. Protein disulfide isomerase (PDI) 9 1.3.1. Thioredoxin domain containing 5 (TXNDC5) 10 1.4. Aim of the study 11 CHAPTER 2. Materials and Methods 12 2.1. Generation of TXNDC5 knockout (KO) mice using CRISPR/Cas9 genome-editing technology 12 2.2. Bleomycin-induced lung fibrosis 13 2.3. Measurement of mice pulmonary function using unrestrained whole body plethysmography and microCT 13 2.4. Histology 14 2.4.1. Immunohistochemistry staining 14 2.4.2. Masson’s Trichrome 15 2.4.3. Picrosirius Red staining 16 2.5. Primary mouse lung fibroblast isolation 16 2.6. Cell line and primary mouse cardiac fibroblasts culture 17 2.7. Lentiviral transduction (KD and OE) 18 2.8. RNA extraction and qRT-PCR 18 2.9. Western blot analysis 19 2.10. Fibroblast proliferation assay 20 2.11. ER stress inhibition assay 20 2.12. Protein disulfide isomerase(PDI) inhibition assay 20 2.13. Immunofluorescent staining for fixed cells 21 2.14. Immunofluorescent staining for tissue sections 21 CHAPTER 3. Results 22 3.1. TXNDC5 is increased in human IPF lung and in bleomycin-induced fibrotic mouse lung 22 3.2. TXNDC5 was strongly induced in both mouse lung fibroblast and human lung fibroblast inresponse to TGFβstimulation 23 3.3. Knocking down TXNDC5 in human lung fibroblast abrogated TGF-β1-induced fibroblast activation and ECM protein, but not mRNA upregulation. 23 3.4. TXNDC5 overexpression increases ECM protein expression 24 3.5. The in vivo role of TXNDC5 in modulating lung fibrosis 24 3.6. Depletion of TXNDC5 decreases the protein expression of SMAD3, STAT3 and p38 phosphorylation 26 3.7. TXNDC5 is regulated by TGFβ-induced ER stress 26 3.8. PDI inhibitor 16F16 ameliorate expression of ECM 27 3.9. Presence of TXNDC5 in cell lineage contributing to the development of pulmonary fibrosis 27 CHAPTER 4. Discussion 28 4.1. Depletion of TXNDC5 decreases the phosphorylation of STAT3 and p38 28 4.2. Knockdown of TXNDC5 attenuates ECM protein production without affecting the mRNA level 29 4.3. TXNDC5 act as a critical role in pulmonary fibrosis and is a potential therapeutic target of pulmonary fibrosis 30 4.4. The existence of TXNDC5 within cell lineage which contributes to pulmonary fibrosis 31 References 33 Figures and Tables. 38 Appendix 64 List of Figures Figure I. Schematic figure illustrating the mechanisms of pulmonary fibrosis[51] . 5 Figure II. The incidence of idiopathic pulmonary fibrosis increases with age[52]. 6 Figure III. The ER stress and UPR pathway[68]. 8 Figure IV. Pathway of ER stress leading to pulmonary fibrosis[68]. 9 Figure 1. TXNDC5 is increased in human IPF and in bleomycin-induced mouse lung. 41 Figure 2. TXNDC5 is highly expressed in both mouse lung fibroblast and human lung fibroblast in response to TGFβ1 stimulation 44 Figure 3. TXNDC5 modulates ECM expression in protein level instead of mRNA level in human lung fibroblast, HPF-a. 48 Figure 4. TXNDC5 overexpression increases ECM protein expression 49 Figure 5. TXNDC5 knockout appears to protect against bleomycin-induced lung fibrosis 52 Figure 6. Depletion of TXNDC5 decreases the protein expression of SMAD3, STAT3 and p38 phosphorylation 55 Figure 7. TXNDC5 is the downstream of TGFβ and ER stress pathway 58 Figure 8. PDI inhibitor 16F16 ameliorates expression of ECM protein 59 Figure 9. TXNDC5 contributing to the development of pulmonary fibrosis exists in the cell lineage of type II pneumocyte 63 List of Tables Table S1. Mouse primer sequence used in this study. 64 Table S2. Human primer sequence used in this study. 65 | |
| dc.language.iso | en | |
| dc.title | 內質網蛋白 TXNDC5（硫氧還蛋白 5）在肺纖維化的角色 | zh_TW |
| dc.title | The Role of ER-Resident Protein TXNDC5 in Pulmonary Fibrosis | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 105-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 施金元(JIN-YUAN SHIH),曹伯年(PO-NIEN TSAO),林泰元(Thai-Yen Ling) | |
| dc.subject.keyword | 肺纖維化,TXNDC5 (硫氧還蛋白5),TGF-β1 (轉化生長因子-β),bleomycin,內質網壓力, | zh_TW |
| dc.subject.keyword | pulmonary fibrosis,Thioredoxin Domain Containing 5 (TXNDC5),endoplasmic reticulum stress (ER stress),TGF β1,bleomycin, | en |
| dc.relation.page | 68 | |
| dc.identifier.doi | 10.6342/NTU201702521 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2017-08-16 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 藥理學研究所 | zh_TW |
| 顯示於系所單位： | 藥理學科所 | |
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