內質網應激：特發性肺纖維化的潛在治療方向_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

王志超 , 馮凡超 , 顧誠 , 彭文潘 , 徐泳 , 韓迪 ,  周賢梅

南京中醫藥大學附屬醫院江蘇省中醫院呼吸科（江蘇南京 210029）;

Corresponding?author：

周賢梅, Email: zhouxianmeijs@aliyun.com

Keywords：

DOI：

10.7507/1671-6205.201905018

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Citation： 王志超, 馮凡超, 顧誠, 彭文潘, 徐泳, 韓迪, 周賢梅. 內質網應激：特發性肺纖維化的潛在治療方向. Chinese Journal of Respiratory and Critical Care Medicine, 2020, 19(5): 520-527. doi: 10.7507/1671-6205.201905018 Copy

1.	Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet, 2017, 389(10082): 1941-1952.
2.	Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med, 2018, 378(19): 1811-1823.
3.	Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol, 2014, 9: 157-179.
4.	Kotton DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med, 2014, 20(8): 822-832.
5.	Barkauskas CE, Cronce MJ, Rackley CR, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest, 2013, 123(7): 3025-3036.
6.	Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012, 302(8): L721-L729.
7.	Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol, 2015, 10: 173-194.
8.	Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta, 2013, 1832(7): 940-947.
9.	Kabore AF, Wang WJ, Russo SJ, et al. Biosynthesis of surfactant protein C: characterization of aggresome formation by EGFP chimeras containing propeptide mutants lacking conserved cysteine residues. J Cell Sci, 2001, 114: 293-302.
10.	Maguire JA, Mulugeta S, Beers MF. Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells. Am J Respir Cell Mol Biol, 2011, 44(3): 404-414.
11.	Zhong Q, Zhou B, Ann DK, et al. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol, 2011, 45(3): 498-509.
12.	Lawson WE, Crossno PF, Polosukhin VV, et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1119-L1126.
13.	Mulugeta S, Maguire JA, Newitt JL, et al. Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms. Am J Physiol Lung Cell Mol Physiol, 2007, 293(3): L720-L729.
14.	Tanjore H, Cheng DS, Degryse AL, et al. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem, 2011, 286(35): 30972-30980.
15.	Korfei M, Ruppert C, Mahavadi P, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2008, 178(8): 838-846.
16.	Guerriero CJ, Brodsky JL. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol Rev, 2012, 92(2): 537-576.
17.	Princiotta MF, Finzi D, Qian SB, et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity, 2003, 18(3): 343-354.
18.	Frakes AE, Dillin A. The UPR(ER): Sensor and Coordinator of Organismal Homeostasis. Mol Cell, 2017, 66(6): 761-771.
19.	Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol, 2017, 13(8): 477-491.
20.	Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer, 2008, 8(11): 851-864.
21.	Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ, 2004, 11(4): 381-389.
22.	Xu C, Ng DT. Glycosylation-directed quality control of protein folding. Nat Rev Mol Cell Biol, 2015, 16(12): 742-752.
23.	Ron D, Harding HP. Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol, 2012, 4(12): pii: a013177.
24.	Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science, 2011, 334(6059): 1081-1086.
25.	Fink AL. Chaperone-mediated protein folding. Physiol Rev, 1999, 79(2): 425-449.
26.	Bulleid NJ. Protein disulfide-isomerase: role in biosynthesis of secretory proteins. Adv Protein Chem, 1993, 44: 125-150.
27.	Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74: 739-789.
28.	Bertolotti A, Zhang Y, Hendershot L M, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol, 2000, 2(6): 326-332.
29.	Moore BB, Moore TA. Viruses in idiopathic pulmonary fibrosis. Etiology and exacerbation. Ann Am Thorac Soc, 2015, 12 Suppl 2: S186-S192.
30.	Kropski JA, Pritchett JM, Zoz DF, et al. Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease. Am J Respir Crit Care Med, 2015, 191(4): 417-426.
31.	Kusko RL, Brothers JF 2nd, Tedrow J, et al. Integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2016, 194(8): 948-960.
32.	Xi Y, Kim T, Brumwell AN, et al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol, 2017, 19(8): 904-914.
33.	Martinez G, Duran-Aniotz C, Cabral-Miranda F, et al. Endoplasmic reticulum proteostasis impairment in aging. Aging Cell, 2017, 16(4): 615-623.
34.	Bueno M, Lai YC, Romero Y, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest, 2015, 125(2): 521-538.
35.	Saez I, Vilchez D. The mechanistic links between proteasome activity, aging and age-related diseases. Curr Genomics, 2014, 15(1): 38-51.
36.	Bratic A, Larsson N G. The role of mitochondria in aging. J Clin Invest, 2013, 123(3): 951-957.
37.	Torres-Gonzalez E, Bueno M, Tanaka A, et al. Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis. Am J Respir Cell Mol Biol, 2012, 46(6): 748-756.
38.	Ruggiano A, Foresti O, Carvalho P. Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol, 2014, 204(6): 869-879.
39.	Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2013, 304(1): L56-L69.
40.	Zhang L, Wang Y, Pandupuspitasari NS, et al. Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis. Am J Transl Res, 2017, 9(2): 722-735.
41.	Cassel TN, Nord M. C/EBP transcription factors in the lung epithelium. Am J Physiol Lung Cell Mol Physiol, 2003, 285(4): L773-L781.
42.	Mccullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol, 2001, 21(4): 1249-1259.
43.	Ma Y, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol, 2002, 318(5): 1351-1365.
44.	Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca²⁺: a control point for apoptosis. Science, 2003, 300(5616): 135-139.
45.	Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature, 2001, 412(6844): 300-307.
46.	Ghavami S, Yeganeh B, Zeki AA, et al. Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol, 2018, 314(3): L493-L504.
47.	Mcmorrow T, Gaffney MM, Slattery C, et al. Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant, 2005, 20(10): 2215-2225.
48.	Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell, 2010, 140(6): 900-917.
49.	Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008, 134(5): 743-756.
50.	Shenderov K, Riteau N, Yip R, et al. Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. J Immunol, 2014, 192(5): 2029-2033.
51.	Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol, 2015, 6: 602.
52.	Yao Y, Wang Y, Zhang Z, et al. Chop deficiency protects mice against bleomycin-induced pulmonary fibrosis by attenuating M2 macrophage production. Mol Ther, 2016, 24(5): 915-925.
53.	Oh J, Riek AE, Weng S, et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem, 2012, 287(15): 11629-11641.
54.	Wang Y, Zhu J, Zhang L, et al. Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor alpha positive feedback loop in M2 macrophages. J Allergy Clin Immunol, 2017, 140(6): 1550-1561, e8.
55.	Lawson WE, Cheng DS, Degryse AL, et al. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A, 2011, 108(26): 10562-10567.
56.	Bridges JP, Wert SE, Nogee LM, et al. Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J Biol Chem, 2003, 278(52): 52739-52746.
57.	Tanaka Y, Ishitsuka Y, Hayasaka M, et al. The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. Pharmacol Res, 2015, 99: 52-62.
58.	Ayaub EA, Kolb PS, Mohammed-Ali Z, et al. GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis. J Pathol, 2016, 239(4): 411-425.
59.	Winters CJ, Koval O, Murthy S, et al. CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis. Am J Physiol Lung Cell Mol Physiol, 2016, 310(1): L86-L94.
60.	Nakajima F, Aratani S, Fujita H, et al. Synoviolin inhibitor LS-102 reduces endoplasmic reticulum stress-induced collagen secretion in an in vitro model of stress-related interstitial pneumonia. Int J Mol Med, 2015, 35(1): 110-116.
61.	Baek HA, Kim DS, Park HS, et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol, 2012, 46(6): 731-739.
62.	Zimmerman KA, Graham LV, Pallero MA, et al. Calreticulin regulates transforming growth factor-beta-stimulated extracellular matrix production. J Biol Chem, 2013, 288(20): 14584-14598.
63.	Hsu HS, Liu CC, Lin JH, et al. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep, 2017, 7(1): 14272.
64.	Byrne AJ, Maher TM, Lloyd CM. Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease?. Trends Mol Med, 2016, 22(4): 303-316.
65.	Ghosh R, Wang L, Wang ES, et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell, 2014, 158(3): 534-548.
66.	Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev, 1998, 12(7): 982-995.
67.	Liu SH, Yang CC, Chan DC, et al. Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro. Oncotarget, 2016, 7(16): 22116-22127.
68.	Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun, 2017, 8: 14532.
69.	Tian Y, Li H, Qiu T, et al. Loss of PTEN induces lung fibrosis via alveolar epithelial cell senescence depending on NF-kappaB activation. Aging Cell, 2019, 18(1): e12858.
70.	Wiley CD, Velarde MC, Lecot P, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab, 2016, 23(2): 303-314.
71.	Williams KW, Liu T, Kong X, et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab, 2014, 20(3): 471-482.
72.	Zhang H, Yue Y, Sun T, et al. Transmissible endoplasmic reticulum stress from myocardiocytes to macrophages is pivotal for the pathogenesis of CVB3-induced viral myocarditis. Sci Rep, 2017, 7: 42162.

1. Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis. Lancet, 2017, 389(10082): 1941-1952.
2. Lederer DJ, Martinez FJ. Idiopathic Pulmonary Fibrosis. N Engl J Med, 2018, 378(19): 1811-1823.
3. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol, 2014, 9: 157-179.
4. Kotton DN, Morrisey EE. Lung regeneration: mechanisms, applications and emerging stem cell populations. Nat Med, 2014, 20(8): 822-832.
5. Barkauskas CE, Cronce MJ, Rackley CR, et al. Type 2 alveolar cells are stem cells in adult lung. J Clin Invest, 2013, 123(7): 3025-3036.
6. Tanjore H, Blackwell TS, Lawson WE. Emerging evidence for endoplasmic reticulum stress in the pathogenesis of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2012, 302(8): L721-L729.
7. Oakes SA, Papa FR. The role of endoplasmic reticulum stress in human pathology. Annu Rev Pathol, 2015, 10: 173-194.
8. Tanjore H, Lawson WE, Blackwell TS. Endoplasmic reticulum stress as a pro-fibrotic stimulus. Biochim Biophys Acta, 2013, 1832(7): 940-947.
9. Kabore AF, Wang WJ, Russo SJ, et al. Biosynthesis of surfactant protein C: characterization of aggresome formation by EGFP chimeras containing propeptide mutants lacking conserved cysteine residues. J Cell Sci, 2001, 114: 293-302.
10. Maguire JA, Mulugeta S, Beers MF. Endoplasmic reticulum stress induced by surfactant protein C BRICHOS mutants promotes proinflammatory signaling by epithelial cells. Am J Respir Cell Mol Biol, 2011, 44(3): 404-414.
11. Zhong Q, Zhou B, Ann DK, et al. Role of endoplasmic reticulum stress in epithelial-mesenchymal transition of alveolar epithelial cells: effects of misfolded surfactant protein. Am J Respir Cell Mol Biol, 2011, 45(3): 498-509.
12. Lawson WE, Crossno PF, Polosukhin VV, et al. Endoplasmic reticulum stress in alveolar epithelial cells is prominent in IPF: association with altered surfactant protein processing and herpesvirus infection. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1119-L1126.
13. Mulugeta S, Maguire JA, Newitt JL, et al. Misfolded BRICHOS SP-C mutant proteins induce apoptosis via caspase-4- and cytochrome c-related mechanisms. Am J Physiol Lung Cell Mol Physiol, 2007, 293(3): L720-L729.
14. Tanjore H, Cheng DS, Degryse AL, et al. Alveolar epithelial cells undergo epithelial-to-mesenchymal transition in response to endoplasmic reticulum stress. J Biol Chem, 2011, 286(35): 30972-30980.
15. Korfei M, Ruppert C, Mahavadi P, et al. Epithelial endoplasmic reticulum stress and apoptosis in sporadic idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2008, 178(8): 838-846.
16. Guerriero CJ, Brodsky JL. The delicate balance between secreted protein folding and endoplasmic reticulum-associated degradation in human physiology. Physiol Rev, 2012, 92(2): 537-576.
17. Princiotta MF, Finzi D, Qian SB, et al. Quantitating protein synthesis, degradation, and endogenous antigen processing. Immunity, 2003, 18(3): 343-354.
18. Frakes AE, Dillin A. The UPR(ER): Sensor and Coordinator of Organismal Homeostasis. Mol Cell, 2017, 66(6): 761-771.
19. Hetz C, Saxena S. ER stress and the unfolded protein response in neurodegeneration. Nat Rev Neurol, 2017, 13(8): 477-491.
20. Wouters BG, Koritzinsky M. Hypoxia signalling through mTOR and the unfolded protein response in cancer. Nat Rev Cancer, 2008, 8(11): 851-864.
21. Oyadomari S, Mori M. Roles of CHOP/GADD153 in endoplasmic reticulum stress. Cell Death Differ, 2004, 11(4): 381-389.
22. Xu C, Ng DT. Glycosylation-directed quality control of protein folding. Nat Rev Mol Cell Biol, 2015, 16(12): 742-752.
23. Ron D, Harding HP. Protein-folding homeostasis in the endoplasmic reticulum and nutritional regulation. Cold Spring Harb Perspect Biol, 2012, 4(12): pii: a013177.
24. Walter P, Ron D. The unfolded protein response: from stress pathway to homeostatic regulation. Science, 2011, 334(6059): 1081-1086.
25. Fink AL. Chaperone-mediated protein folding. Physiol Rev, 1999, 79(2): 425-449.
26. Bulleid NJ. Protein disulfide-isomerase: role in biosynthesis of secretory proteins. Adv Protein Chem, 1993, 44: 125-150.
27. Schroder M, Kaufman RJ. The mammalian unfolded protein response. Annu Rev Biochem, 2005, 74: 739-789.
28. Bertolotti A, Zhang Y, Hendershot L M, et al. Dynamic interaction of BiP and ER stress transducers in the unfolded-protein response. Nat Cell Biol, 2000, 2(6): 326-332.
29. Moore BB, Moore TA. Viruses in idiopathic pulmonary fibrosis. Etiology and exacerbation. Ann Am Thorac Soc, 2015, 12 Suppl 2: S186-S192.
30. Kropski JA, Pritchett JM, Zoz DF, et al. Extensive phenotyping of individuals at risk for familial interstitial pneumonia reveals clues to the pathogenesis of interstitial lung disease. Am J Respir Crit Care Med, 2015, 191(4): 417-426.
31. Kusko RL, Brothers JF 2nd, Tedrow J, et al. Integrated genomics reveals convergent transcriptomic networks underlying chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Am J Respir Crit Care Med, 2016, 194(8): 948-960.
32. Xi Y, Kim T, Brumwell AN, et al. Local lung hypoxia determines epithelial fate decisions during alveolar regeneration. Nat Cell Biol, 2017, 19(8): 904-914.
33. Martinez G, Duran-Aniotz C, Cabral-Miranda F, et al. Endoplasmic reticulum proteostasis impairment in aging. Aging Cell, 2017, 16(4): 615-623.
34. Bueno M, Lai YC, Romero Y, et al. PINK1 deficiency impairs mitochondrial homeostasis and promotes lung fibrosis. J Clin Invest, 2015, 125(2): 521-538.
35. Saez I, Vilchez D. The mechanistic links between proteasome activity, aging and age-related diseases. Curr Genomics, 2014, 15(1): 38-51.
36. Bratic A, Larsson N G. The role of mitochondria in aging. J Clin Invest, 2013, 123(3): 951-957.
37. Torres-Gonzalez E, Bueno M, Tanaka A, et al. Role of endoplasmic reticulum stress in age-related susceptibility to lung fibrosis. Am J Respir Cell Mol Biol, 2012, 46(6): 748-756.
38. Ruggiano A, Foresti O, Carvalho P. Quality control: ER-associated degradation: protein quality control and beyond. J Cell Biol, 2014, 204(6): 869-879.
39. Araya J, Kojima J, Takasaka N, et al. Insufficient autophagy in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2013, 304(1): L56-L69.
40. Zhang L, Wang Y, Pandupuspitasari NS, et al. Endoplasmic reticulum stress, a new wrestler, in the pathogenesis of idiopathic pulmonary fibrosis. Am J Transl Res, 2017, 9(2): 722-735.
41. Cassel TN, Nord M. C/EBP transcription factors in the lung epithelium. Am J Physiol Lung Cell Mol Physiol, 2003, 285(4): L773-L781.
42. Mccullough KD, Martindale JL, Klotz LO, et al. Gadd153 sensitizes cells to endoplasmic reticulum stress by down-regulating Bcl2 and perturbing the cellular redox state. Mol Cell Biol, 2001, 21(4): 1249-1259.
43. Ma Y, Brewer JW, Diehl JA, et al. Two distinct stress signaling pathways converge upon the CHOP promoter during the mammalian unfolded protein response. J Mol Biol, 2002, 318(5): 1351-1365.
44. Scorrano L, Oakes SA, Opferman JT, et al. BAX and BAK regulation of endoplasmic reticulum Ca²⁺: a control point for apoptosis. Science, 2003, 300(5616): 135-139.
45. Reimold AM, Iwakoshi NN, Manis J, et al. Plasma cell differentiation requires the transcription factor XBP-1. Nature, 2001, 412(6844): 300-307.
46. Ghavami S, Yeganeh B, Zeki AA, et al. Autophagy and the unfolded protein response promote profibrotic effects of TGF-β₁ in human lung fibroblasts. Am J Physiol Lung Cell Mol Physiol, 2018, 314(3): L493-L504.
47. Mcmorrow T, Gaffney MM, Slattery C, et al. Cyclosporine A induced epithelial-mesenchymal transition in human renal proximal tubular epithelial cells. Nephrol Dial Transplant, 2005, 20(10): 2215-2225.
48. Hotamisligil GS. Endoplasmic reticulum stress and the inflammatory basis of metabolic disease. Cell, 2010, 140(6): 900-917.
49. Kaser A, Lee AH, Franke A, et al. XBP1 links ER stress to intestinal inflammation and confers genetic risk for human inflammatory bowel disease. Cell, 2008, 134(5): 743-756.
50. Shenderov K, Riteau N, Yip R, et al. Cutting edge: Endoplasmic reticulum stress licenses macrophages to produce mature IL-1beta in response to TLR4 stimulation through a caspase-8- and TRIF-dependent pathway. J Immunol, 2014, 192(5): 2029-2033.
51. Braga TT, Agudelo JS, Camara NO. Macrophages during the fibrotic process: M2 as friend and foe. Front Immunol, 2015, 6: 602.
52. Yao Y, Wang Y, Zhang Z, et al. Chop deficiency protects mice against bleomycin-induced pulmonary fibrosis by attenuating M2 macrophage production. Mol Ther, 2016, 24(5): 915-925.
53. Oh J, Riek AE, Weng S, et al. Endoplasmic reticulum stress controls M2 macrophage differentiation and foam cell formation. J Biol Chem, 2012, 287(15): 11629-11641.
54. Wang Y, Zhu J, Zhang L, et al. Role of C/EBP homologous protein and endoplasmic reticulum stress in asthma exacerbation by regulating the IL-4/signal transducer and activator of transcription 6/transcription factor EC/IL-4 receptor alpha positive feedback loop in M2 macrophages. J Allergy Clin Immunol, 2017, 140(6): 1550-1561, e8.
55. Lawson WE, Cheng DS, Degryse AL, et al. Endoplasmic reticulum stress enhances fibrotic remodeling in the lungs. Proc Natl Acad Sci U S A, 2011, 108(26): 10562-10567.
56. Bridges JP, Wert SE, Nogee LM, et al. Expression of a human surfactant protein C mutation associated with interstitial lung disease disrupts lung development in transgenic mice. J Biol Chem, 2003, 278(52): 52739-52746.
57. Tanaka Y, Ishitsuka Y, Hayasaka M, et al. The exacerbating roles of CCAAT/enhancer-binding protein homologous protein (CHOP) in the development of bleomycin-induced pulmonary fibrosis and the preventive effects of tauroursodeoxycholic acid (TUDCA) against pulmonary fibrosis in mice. Pharmacol Res, 2015, 99: 52-62.
58. Ayaub EA, Kolb PS, Mohammed-Ali Z, et al. GRP78 and CHOP modulate macrophage apoptosis and the development of bleomycin-induced pulmonary fibrosis. J Pathol, 2016, 239(4): 411-425.
59. Winters CJ, Koval O, Murthy S, et al. CaMKII inhibition in type II pneumocytes protects from bleomycin-induced pulmonary fibrosis by preventing Ca2+-dependent apoptosis. Am J Physiol Lung Cell Mol Physiol, 2016, 310(1): L86-L94.
60. Nakajima F, Aratani S, Fujita H, et al. Synoviolin inhibitor LS-102 reduces endoplasmic reticulum stress-induced collagen secretion in an in vitro model of stress-related interstitial pneumonia. Int J Mol Med, 2015, 35(1): 110-116.
61. Baek HA, Kim DS, Park HS, et al. Involvement of endoplasmic reticulum stress in myofibroblastic differentiation of lung fibroblasts. Am J Respir Cell Mol Biol, 2012, 46(6): 731-739.
62. Zimmerman KA, Graham LV, Pallero MA, et al. Calreticulin regulates transforming growth factor-beta-stimulated extracellular matrix production. J Biol Chem, 2013, 288(20): 14584-14598.
63. Hsu HS, Liu CC, Lin JH, et al. Involvement of ER stress, PI3K/AKT activation, and lung fibroblast proliferation in bleomycin-induced pulmonary fibrosis. Sci Rep, 2017, 7(1): 14272.
64. Byrne AJ, Maher TM, Lloyd CM. Pulmonary macrophages: a new therapeutic pathway in fibrosing lung disease?. Trends Mol Med, 2016, 22(4): 303-316.
65. Ghosh R, Wang L, Wang ES, et al. Allosteric inhibition of the IRE1alpha RNase preserves cell viability and function during endoplasmic reticulum stress. Cell, 2014, 158(3): 534-548.
66. Zinszner H, Kuroda M, Wang X, et al. CHOP is implicated in programmed cell death in response to impaired function of the endoplasmic reticulum. Genes Dev, 1998, 12(7): 982-995.
67. Liu SH, Yang CC, Chan DC, et al. Chemical chaperon 4-phenylbutyrate protects against the endoplasmic reticulum stress-mediated renal fibrosis in vivo and in vitro. Oncotarget, 2016, 7(16): 22116-22127.
68. Schafer MJ, White TA, Iijima K, et al. Cellular senescence mediates fibrotic pulmonary disease. Nat Commun, 2017, 8: 14532.
69. Tian Y, Li H, Qiu T, et al. Loss of PTEN induces lung fibrosis via alveolar epithelial cell senescence depending on NF-kappaB activation. Aging Cell, 2019, 18(1): e12858.
70. Wiley CD, Velarde MC, Lecot P, et al. Mitochondrial dysfunction induces senescence with a distinct secretory phenotype. Cell Metab, 2016, 23(2): 303-314.
71. Williams KW, Liu T, Kong X, et al. Xbp1s in Pomc neurons connects ER stress with energy balance and glucose homeostasis. Cell Metab, 2014, 20(3): 471-482.
72. Zhang H, Yue Y, Sun T, et al. Transmissible endoplasmic reticulum stress from myocardiocytes to macrophages is pivotal for the pathogenesis of CVB3-induced viral myocarditis. Sci Rep, 2017, 7: 42162.

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內質網應激：特發性肺纖維化的潛在治療方向

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