吲哚-3-原醇对博莱霉素致小鼠/大鼠肺纤维化的干预作用及其机制研究
|
摘要
目的观察吲哚-3-原醇（Indole-3-carbinol，I3C）对博莱霉素（Bleomycin, BLM）致小鼠和大鼠肺纤维化的干预作用并初步探讨其机制。
方法ICR小鼠随机分为6组：正常组、模型组、醋酸泼尼松组（6.67mg·kg~(-1)）、I3C小、中、大剂量组（25、50、100mg·kg~(-1)）；SD大鼠随机分为6组：正常组、模型组、醋酸泼尼松组（3.34mg·kg~(-1)）、I3C小、中、大剂量组（12.5、25、50mg·kg~(-1)）。通过气管内注射BLM制备肺纤维化模型，造模后第二天治疗组动物分别给予泼尼松和不同剂量的I3C，每天一次。连续给药28天处死动物，称其体重、计算肺系数；紫外分光光度计检测血清和肺组织羟脯氨酸（Hydroxyproline，HYP）含量、血清和肺组织总抗氧化能力（Total antioxidative capacity，T-AOC）水平；取固定部位肺组织切片HE和Masson染色，光镜下进行病理学观察；电镜观察大鼠肺组织超微结构变化；ELISA法检测大鼠肺泡灌洗液中IL-1β和IL-6的含量；RT-PCR法检测肺组织中α-SMA、Collagen I、TGF-β1、Smad2、Smad7mRNA的表达；Real Time RT-PCR法检测大鼠肺组织miRNA-21、Let-7d的表达；Western blot法检测肺组织中α-SMA、Vimentin、Caveolin-1、TGF-β1、Smad2蛋白的表达。
结果I3C给药28天后，肺纤维化小鼠/大鼠的血清和肺组织T-AOC水平明显提高（P<0.05，P<0.01），肺系数、血清和肺组织HYP含量明显降低（P<0.05，P<0.01）；I3C组大鼠肺泡灌洗液中IL-1β和IL-6的含量明显降低（P<0.05，P<0.01）；光镜观察表明I3C组肺纤维化小鼠/大鼠肺泡炎和肺纤维化程度明显降低（P<0.05，P<0.01）；RT-PCR检测发现I3C组肺组织α-SMA、Collagen I、TGF-β1、Smad2基因水平明显下调， Smad7基因表达明显上调（P<0.05，P<0.01）；Real Time RT-PCR检测发现I3C组大鼠miRNA-21表达明显下调，Let-7d的表达明显上调（P<0.05，P<0.01）；Western blot分析结果表明I3C组小鼠/大鼠肺组织α-SMA、Vimentin、TGF-β1、Smad2蛋白表达明显下调（P<0.05，P<0.01），Caveolin-1蛋白表达上调。
结论I3C对BLM致肺纤维化小鼠/大鼠可提高机体总抗氧化能力、减少炎症因子产生、减少细胞间质胶原沉积，具有一定的抗肺纤维化作用，该作用机制可能与其调控TGF-β1/Smad信号通路有关。
Objective: To investigate the effects and mechanisms of indole-3-carbinol (I3C) onbleomycin-induced pulmonary fibrosis in mice and rats.
Methods: The ICR mice were divided into six groups randomly：control group, modelgroup, prednisolone group(6.67mg·kg~(-1)) and I3C low-dose (25mg·kg~(-1)), middle-dose (50mg·kg~(-1)), high-dose group (100mg·kg~(-1)). The SD rats were divided into six groupsrandomly：control group, model group, prednisolone group (3.34mg·kg~(-1)) and I3Clow-dose (12.5mg·kg~(-1)), middle-dose (25mg·kg~(-1)), high-dose group (50mg·kg~(-1)).Pulmonary fibrosis model was replicated by single intratracheal injection of bleomycin. Inthe next day, the animals were treated by intragastric administration once a day. After28days, the animals were sacrificed. The lung index and the levels of T-AOC and HYP weremeasured, and the pathologic changes of the lung tissue were obtained by HE and Massonstaining. The levels of IL-1β and IL-6in bronchoalveolar lavage fluid were assayed byELISA. The levels of α-SMA, Collagen I, TGF-β1, Smad2and Smad7mRNA wereassayed by RT-PCR. The levels of miRNA-21and Let-7d were assayed by Real TimeRT-PCR. The levels of α-SMA, Vimentin, Caveolin-1, TGF-β1and Smad2protein wereanalyzed by western blot.
Results: I3C improved the activity of T-AOC in serum, and reduced pulmonary indexand the content of HYP as well(P<0.05or P<0.01); the alveolitis and fibrosis extent wereattenuated significantly(P<0.05or P<0.01); the levels of IL-1β and IL-6inbronchoalveolar lavage fluid were decreased significantly; the levels of TGF-β1, Smad2,Vimentin, α-SMA and Collagen I were all decreased significantly(P<0.05or P<0.01);thelevels of Caveolin-1and Smad7were all increased significantly(P<0.05or P<0.01); thelevel of miRNA-21was decreased significantly, while the level of Let-7d was increasedremarkably(P<0.05or P<0.01).
Conclusion: I3C could attenuate bleomycin-induced pulmonary fibrosis in mice and rats. The mechanisms might be related with the anti-oxidatant, the anti-inflammatory,inhibition of collagen formation and the regulation of TGF-β1/Smad signal pathway.
方法ICR小鼠随机分为6组：正常组、模型组、醋酸泼尼松组（6.67mg·kg~(-1)）、I3C小、中、大剂量组（25、50、100mg·kg~(-1)）；SD大鼠随机分为6组：正常组、模型组、醋酸泼尼松组（3.34mg·kg~(-1)）、I3C小、中、大剂量组（12.5、25、50mg·kg~(-1)）。通过气管内注射BLM制备肺纤维化模型，造模后第二天治疗组动物分别给予泼尼松和不同剂量的I3C，每天一次。连续给药28天处死动物，称其体重、计算肺系数；紫外分光光度计检测血清和肺组织羟脯氨酸（Hydroxyproline，HYP）含量、血清和肺组织总抗氧化能力（Total antioxidative capacity，T-AOC）水平；取固定部位肺组织切片HE和Masson染色，光镜下进行病理学观察；电镜观察大鼠肺组织超微结构变化；ELISA法检测大鼠肺泡灌洗液中IL-1β和IL-6的含量；RT-PCR法检测肺组织中α-SMA、Collagen I、TGF-β1、Smad2、Smad7mRNA的表达；Real Time RT-PCR法检测大鼠肺组织miRNA-21、Let-7d的表达；Western blot法检测肺组织中α-SMA、Vimentin、Caveolin-1、TGF-β1、Smad2蛋白的表达。
结果I3C给药28天后，肺纤维化小鼠/大鼠的血清和肺组织T-AOC水平明显提高（P<0.05，P<0.01），肺系数、血清和肺组织HYP含量明显降低（P<0.05，P<0.01）；I3C组大鼠肺泡灌洗液中IL-1β和IL-6的含量明显降低（P<0.05，P<0.01）；光镜观察表明I3C组肺纤维化小鼠/大鼠肺泡炎和肺纤维化程度明显降低（P<0.05，P<0.01）；RT-PCR检测发现I3C组肺组织α-SMA、Collagen I、TGF-β1、Smad2基因水平明显下调， Smad7基因表达明显上调（P<0.05，P<0.01）；Real Time RT-PCR检测发现I3C组大鼠miRNA-21表达明显下调，Let-7d的表达明显上调（P<0.05，P<0.01）；Western blot分析结果表明I3C组小鼠/大鼠肺组织α-SMA、Vimentin、TGF-β1、Smad2蛋白表达明显下调（P<0.05，P<0.01），Caveolin-1蛋白表达上调。
结论I3C对BLM致肺纤维化小鼠/大鼠可提高机体总抗氧化能力、减少炎症因子产生、减少细胞间质胶原沉积，具有一定的抗肺纤维化作用，该作用机制可能与其调控TGF-β1/Smad信号通路有关。
Objective: To investigate the effects and mechanisms of indole-3-carbinol (I3C) onbleomycin-induced pulmonary fibrosis in mice and rats.
Methods: The ICR mice were divided into six groups randomly：control group, modelgroup, prednisolone group(6.67mg·kg~(-1)) and I3C low-dose (25mg·kg~(-1)), middle-dose (50mg·kg~(-1)), high-dose group (100mg·kg~(-1)). The SD rats were divided into six groupsrandomly：control group, model group, prednisolone group (3.34mg·kg~(-1)) and I3Clow-dose (12.5mg·kg~(-1)), middle-dose (25mg·kg~(-1)), high-dose group (50mg·kg~(-1)).Pulmonary fibrosis model was replicated by single intratracheal injection of bleomycin. Inthe next day, the animals were treated by intragastric administration once a day. After28days, the animals were sacrificed. The lung index and the levels of T-AOC and HYP weremeasured, and the pathologic changes of the lung tissue were obtained by HE and Massonstaining. The levels of IL-1β and IL-6in bronchoalveolar lavage fluid were assayed byELISA. The levels of α-SMA, Collagen I, TGF-β1, Smad2and Smad7mRNA wereassayed by RT-PCR. The levels of miRNA-21and Let-7d were assayed by Real TimeRT-PCR. The levels of α-SMA, Vimentin, Caveolin-1, TGF-β1and Smad2protein wereanalyzed by western blot.
Results: I3C improved the activity of T-AOC in serum, and reduced pulmonary indexand the content of HYP as well(P<0.05or P<0.01); the alveolitis and fibrosis extent wereattenuated significantly(P<0.05or P<0.01); the levels of IL-1β and IL-6inbronchoalveolar lavage fluid were decreased significantly; the levels of TGF-β1, Smad2,Vimentin, α-SMA and Collagen I were all decreased significantly(P<0.05or P<0.01);thelevels of Caveolin-1and Smad7were all increased significantly(P<0.05or P<0.01); thelevel of miRNA-21was decreased significantly, while the level of Let-7d was increasedremarkably(P<0.05or P<0.01).
Conclusion: I3C could attenuate bleomycin-induced pulmonary fibrosis in mice and rats. The mechanisms might be related with the anti-oxidatant, the anti-inflammatory,inhibition of collagen formation and the regulation of TGF-β1/Smad signal pathway.
引文
[1]Kim T H, Kim S H, Seo J Y, et al. Blockade of the Wnt/β-Catenin Pathway AttenuatesBleomycin-Induced Pulmonary Fibrosis [J]. The Tohoku journal of experimentalmedicine,2011,223(1):45-54.
[2]Fernandez I E, Eickelberg O. New cellular and molecular mechanisms of lung injuryand fibrosis in idiopathic pulmonary fibrosis[J]. The Lancet,2012,380(9842):680-688.
[3]Richeldi L, Davies H R, Ferrara G, et al. Corticosteroids for idiopathic pulmonaryfibrosis [J]. Cochrane Database Syst Rev,2003,3.
[4]Luppi F, Cerri S, Beghe B, et al. Corticosteroid and immunomodulatory agents inidiopathic pulmonary fibrosis[J]. Respiratory medicine,2004,98(11):1035-1044.
[5]Scotton C J, Chambers R C. Molecular Targets in Pulmonary FibrosisTheMyofibroblast in Focus [J]. CHEST Journal,2007,132(4):1311-1321.
[6]Bringardner B D, Baran C P, Eubank T D, et al. The role of inflammation in thepathogenesis of idiopathic pulmonary fibrosis [J]. Antioxidants&redox signaling,2008,10(2):287.
[7]Papaharalambus C A, Griendling K K. Basic mechanisms of oxidative stress andreactive oxygen species in cardiovascular injury [J]. Trends in cardiovascular medicine,2007,17(2):48-54.
[8]Wadsworth R M. Oxidative stress and the endothelium [J]. Experimental Physiology,2008,93(1):155-157.
[9]Kliment C R, Englert J M, Gochuico B R, et al. Oxidative stress alters syndecan-1distribution in lungs with pulmonary fibrosis [J]. Journal of Biological Chemistry,2009,284(6):3537-3545.
[10] Wynn T A. Integrating mechanisms of pulmonary fibrosis [J]. The Journal ofExperimental Medicine,2011,208(7):1339-1350.
[11] Morrisey E E. Wnt signaling and pulmonary fibrosis [J]. The American journal ofpathology,2003,162(5):1393.
[12] Fitch P M, Wakelin S J, Lowrey J A, et al. Shh expression in pulmonary injury anddisease[J]. Hedgehog-Gli Signaling in Human Disease,2006:119-128.
[13] Aoyagi-Ikeda K, Maeno T, Matsui H, et al. Notch induces myofibroblastdifferentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3pathway[J]. American journal of respiratory cell and molecular biology,2011,45(1):136.
[14]Crosby L M, Waters C M. Epithelial repair mechanisms in the lung [J]. AmericanJournal of Physiology-Lung Cellular and Molecular Physiology,2010,298(6):715-731.
[15] Selman M, King T E, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolvinghypotheses about its pathogenesis and implications for therapy[J]. Annals of InternalMedicine,2001,134(2):136-151.
[16] Willis B C, Borok Z. TGF-β-induced EMT: mechanisms and implications for fibroticlung disease [J]. American Journal of Physiology-Lung Cellular and MolecularPhysiology,2007,293(3): L525-L534.
[17]Hashimoto N, Phan S H, Imaizumi K, et al. Endothelial–mesenchymal transition inbleomycin-induced pulmonary fibrosis [J]. American journal of respiratory cell andmolecular biology,2010,43(2):161.
[18] Wynn T A, Ramalingam T R. Mechanisms of fibrosis: therapeutic translation forfibrotic disease [J]. Nature medicine,2012,18(7):1028-1040.
[19] Jones M G. Triple therapy for idiopathic pulmonary fibrosis[J]. Thorax,2012.
[20]Raghu G, Anstrom K J, King Jr T E, et al. Prednisone, azathioprine, andN-acetylcysteine for pulmonary fibrosis[J]. The New England journal of medicine,2012,366(21):1968.
[21]Park S, Lee E J. Recent Advances in Idiopathic Pulmonary Fibrosis[J]. Tuberculosisand respiratory diseases,2013,74(1):1-6.
[22] Karihaloo A. Anti-Fibrosis Therapy and Diabetic Nephropathy [J]. Current DiabetesReports,2012:1-9.
[23]Potts J, Yogaratnam D. Pirfenidone: A Novel Agent for the Treatment of IdiopathicPulmonary Fibrosis[J]. The Annals of pharmacotherapy,2013,47(3):361-367.
[24] Raghu G, Collard H R, Egan J J, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis andmanagement [J]. American Journal of Respiratory and Critical Care Medicine,2011,183(6):788-824.
[25] Salhi B, Troosters T, Behaegel M, et al. Effects of pulmonary rehabilitation in patientswith restrictive lung diseases [J]. CHEST Journal,2010,137(2):273-279.
[26] Fang A, Studer S, Kawut S M, et al. Elevated pulmonary artery pressure is a riskfactor for primary graft dysfunction following lung transplantation for idiopathicpulmonary fibrosis[J]. CHEST Journal,2011,139(4):782-787.
[27] Lota H K, Wells A U. The evolving pharmacotherapy of pulmonary fibrosis [J].Expert opinion on pharmacotherapy,2013,14(1):79-89.
[28] Hogaboam C, Kunkel S L, Trujillo G. Biomakers predictive of progression of fibrosis:U.S. Patent20,120,282,276[P].2012-11-8.
[29] Aggarwal B B, Ichikawa H. Molecular targets and anticancer potential ofindole-3-carbinol and its derivatives [J].Cell Cycle,2005,4(9):1201-1215．
[30] Shimamoto K, Hayashi H, Taniai E, et al. Antioxidant N-acetyl-L-cysteine (NAC)supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumorpromotion of indole-3-carbinol (I3C) in rats[J]. The Journal of toxicological sciences,2011,36(6):775-786.
[31] Shen A, Zhang B, Ping J, et al. In vivo study on the protection of indole-3-carbinol(I3C) against the mouse acute alcoholic liver injury by micro-Raman spectroscopy [J].Journal of Raman Spectroscopy,2009,40(5):550-555.
[32] Guo Y, Wu X Q, Zhang C, et al. Effect of indole-3-carbinol on ethanol-induced liverinjury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cutrat liver slices [J]. Clinical and Experimental Pharmacology and Physiology,2010,37(12):1107-1113.
[33] Ping J, Li J, Liao Z, et al. Indole-3-carbinol inhibits hepatic stellate cells proliferationby blocking NADPH oxidase/reactive oxygen species/p38MAPK pathway [J].European journal of pharmacology,2011,650(2):656-662.
[34]Gao A M, Ping J, Wang H. Therapeutic effects of indole-3-carbinol on multiplehepatotoxic factors-induced liver fibrosis in rats [J]. Chinese Pharmacological Bulletin,2011,27(6):764-769.
[35]Ping J, Gao A M, Xu D, et al. Therapeutic effect of indole-3-carbinol on pigserum-induced hepatic fibrosis in rats [J]. Acta Pharmaceutica Sinica2011,46(8):915-921
[36] Szapiel S V, Elson N A, Fulmer J D, et al. Bleomycin-induced interstitial pulmonarydisease in the nude, athymic mouse[J]. The American review of respiratory disease,1979,120(4):893.
[37] Hubner RH, Gitter W, El MN, et al. Standardized quantification of pulmonary fibrosisin histological samples[J].Biotechniques,2008,44(4):507-511,514-517.
[38] Sriram N, Kalayarasan, Sudhandiran G. Enhancement of antioxidant defense systemby epigallocatechin-3-gallate during bleomycin induced experimental pulmonaryfibrosis [J]. Biol Pharm Bull,2008,31(7):1306-1311.
[39] Lacerda A C R, Rodrigues-Machado M G, Mendes P L, et al. Paraquat (PQ)-inducedpulmonary fibrosis increases exercise metabolic cost, reducing aerobic performance inrats[J]. The Journal of toxicological sciences,2009,34(6):671-679.
[40] Nagatani Y, Nitta N, Otani H, et al. Quantitative Measurement of Bleomycin inducedLung Fibrosis in Rabbits Using Sequential in vivo Regional Analysis andHigh-Resolution Computed Tomography:Correlation with Pathologic Findings[J].Academic Radiology,2011,18(6):672-681.
[41] Rashidi I, Mozaffari A R. Bleomycin Induced Pulmonary Fibrosis [J]. MJIRC,2005,7(3).
[42] Liu R, Ahmed K M, Nantajit D, et al. Therapeutic effects of alpha-lipoic acid onbleomycin-induced pulmonary fibrosis in rats[J]. International journal of molecularmedicine,2007,19(6):865.
[43] Li Guangming, Lei Jianping, Zeng Jianer. Inflammation cells, cytokines andpulmonary fibrosis in Bronchoalveolar lavage fluid[J]. Journal of Jianxi medicine,2010,45(12):1251-1253.
[44] Kolb M, Margetts P J, Anthony D C, et al. Transient expression of IL-1beta inducesacute lung injury and chronic repair leading to pulmonary fibrosis[J]. Journal ofClinical Investigation,2001,107(12):1529-1544.
[45] Uyttenhove C, Van Snick J. Development of an anti-IL-17A auto-vaccine thatprevents experimental auto-immune encephalomyelitis [J].European journal ofimmunology,2006,36(11).
[46] Crosby L M, Waters C M. Epithelial repair mechanisms in the lung[J]. AmericanJournal of Physiology-Lung Cellular and Molecular Physiology,2010,298(6):715-731.
[47] Nakerakanti S, Trojanowska M. Suppl1: The Role of TGF-β Receptors in Fibrosis[J].The Open Rheumatology Journal,2012,6:156.
[48] Thannickal V J, Horowitz J C. Evolving concepts of apoptosis in idiopathicpulmonary fibrosis[J]. Proceedings of the American Thoracic Society,2006,3(4):350-356.
[49] Guéders M, Foidart J M, Noel A, et al. Matrix metalloproteinases (MMPs) and tissueinhibitors of MMPs in the respiratory tract: potential implications in asthma and otherlung diseases[J]. European journal of pharmacology,2006,533(1-3):133-144.
[50] Kinnula V L, Fattman C L, Tan R J, et al. Oxidative Stress in Pulmonary Fibrosis APossible Role for Redox Modulatory Therapy[J]. American journal of respiratory andcritical care medicine,2005,172(4):417-422.
[51]Pan J, Su Y, Hou X, et al. Protective effect of recombinant protein SOD-TAT onradiation-induced lung injury in mice [J]. Life Sciences,2012.
[52]Xu H, Hao Y, Su Y, et al. Effect of Soyasaponin on Expression of Fas/FasL ofPneumonocyte in Silicotic Fibrosis Rats[M].Informatics and Management Science I.Springer London,2013:309-313.
[53] Pittet J F, Griffiths M J D, Geiser T, et al. TGF-beta is a critical mediator of acute lunginjury[J]. Journal of Clinical Investigation,2001,107(12):1537-1562.
[54] Challen G A, Boles N C, Chambers S M, et al. Distinct hematopoietic stem cellsubtypes are differentially regulated by TGF-β1[J]. Cell Stem Cell,2010,6(3):265-278.
[55] Qu L, Liu A, Zhou L, et al. Clinical and molecular effects on mature burn scars aftertreatment with a fractional CO2laser [J]. Lasers in Surgery and Medicine,2012.
[56] Usuki J,Matsuda K,Azuma A, et al. Sequential analysis of myofibroblastdifferentiation and transforming growth factor-beta1/Smad pathway activation inmurine pulmonary fibrosis[J].J Nihon Med Sch,2012,79(1):46-59.
[57] Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications forfibrotic lung disease [J].Am J Physiol Lung Cell Mol Physiol,2007,293(3):525-534.
[58] Ma R L, Wang W P, Jiang X G, et al. Effects of total flavonoids of scutellariabaicalensis georgi(TFSB) on bleomycin-induced pulmonary fibrosis in rats[J].ChinesePharmacological Bulletin,2011,27(4):537-542.
[59] Sobral L M, Montan P F, Zecchin K G, et al. Smad7Blocks Transforming GrowthFactor-β1–Induced Gingival Fibroblast–Myofibroblast Transition via InhibitoryRegulation of Smad2and Connective Tissue Growth Factor[J]. Journal ofPeriodontology,2011,82(4):642-651.
[60]Shivshankar P, Brampton C, Miyasato S, et al. Caveolin-1deficiency protects frompulmonary fibrosis by modulating epithelial cell senescence in mice[J]. Am J RespirCell Mol Biol,2012,47(1):28-36.
[61]Ghosh A K, Vaughan D E. PAI-1in tissue fibrosis[J]. Journal of cellular physiology,2012,227(2):493-507.
[62]King T E, Pardo A, Selman M. Idiopathic pulmonary fibrosis[J]. The Lancet,2011,378(9807):1949-1961.
[63] Tourkina E, Richard M, G z P, et al. Antifibrotic properties of caveolin-1scaffolding domain in vitro and in vivo[J]. American Journal of Physiology-LungCellular and Molecular Physiology,2008,294(5):843-861.
[64] Razani B, Zhang X L, Bitzer M, et al. Caveolin-1regulates transforming growthfactor (TGF)-β/SMAD signaling through an interaction with the TGF-β type Ireceptor[J]. Journal of Biological Chemistry,2001,276(9):6727-6738.
[65] Lee E K, Lee Y S, Han I O, et al. Expression of Caveolin-1reduces cellular responsesto TGF-β1through down-regulating the expression of TGF-β type II receptor gene inNIH3T3fibroblast cells[J]. Biochemical and biophysical research communications,2007,359(2):385-390
[66] Tuschl T, Lagos-quintana M, Lendeckel W, et al. MicroRNA molecules: EuropeanPatent EP2428571[P].2012-3-14.
[67]J Jiang X, Tsitsiou E, Herrick S E, et al. MicroRNAs and the regulation of fibrosis[J].FEBS Journal,2010,277(9):2015-2021.
[68]Yang I V. Epigenomics of idiopathic pulmonary fibrosis[J]. Epigenomics,2012,4(2):195-203.
[69] Frankel L B, Christoffersen N R, Jacobsen A, et al. Programmed cell death4(PDCD4)is an important functional target of the microRNA miR-21in breast cancer cells[J].Journal of Biological Chemistry,2008,283(2):1026-1033.
[70]Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21regulates expression of thePTEN tumor suppressor gene in human hepatocellular cancer[J]. Gastroenterology,2007,133(2):647.
[71]Parasramka M A, Ho E, Williams D E, et al. MicroRNAs, diet, and cancer: newmechanistic insights on the epigenetic actions of phytochemicals[J]. Molecularcarcinogenesis,2011,51(3):213-230.
[72] Roy S, Khanna S, Hussain S R A, et al. MicroRNA expression in response to murinemyocardial infarction: miR-21regulates fibroblast metalloprotease-2via phosphataseand tensin homologue[J]. Cardiovascular research,2009,82(1):21-29.
[73] Bauersachs J. miR-21: a central regulator of fibrosis not only in the broken heart[J].Cardiovascular Research,2012
[74]Liu G, Friggeri A, Yang Y, et al. miR-21mediates fibrogenic activation of pulmonaryfibroblasts and lung fibrosis[J]. The Journal of experimental medicine,2010,207(8):1589-1597.
[75]Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial disease bystimulating MAP kinase signalling in fibroblasts[J]. Nature,2008,456(7224):980-984.
[76]Bhagat T D, Zhou L, Sokol L, et al. miR-21mediates hematopoietic suppression inMDS by activating TGF-β signaling [J]. Blood,2013.
[77] Liu G, Friggeri A, Yang Y, et al. miR-21mediates fibrogenic activation of pulmonaryfibroblasts and lung fibrosis[J]. The Journal of experimental medicine,2010,207(8):1589-1597.
[78]Wang Y, Hu X, Greshock J, et al. Genomic DNA Copy-Number Alterations of thelet-7Family in Human Cancers[J]. PloS one,2012,7(9): e44399.
[79]Rabinovich E I, Selman M, Kaminski N. Epigenomics of Idiopathic PulmonaryFibrosis Evaluating the First Steps[J]. American Journal of Respiratory and CriticalCare Medicine,2012,186(6):473-475.
[80] Pandit K V, Corcoran D, Yousef H, et al. Inhibition and role of let-7d in idiopathicpulmonary fibrosis[J]. American journal of respiratory and critical care medicine,2010,182(2):220-229.
[81] Blahna M T, Hata A. Smad-mediated regulation of microRNA biosynthesis[J]. FEBSletters,2012,586(14):1906-1912.
[82] Peter M E. Let-7and miR-200microRNAs: guardians against pluripotency and cancerprogression[J]. Cell Cycle,2009,8(6):843-852.
[83] Lino Cardenas C L, Kaminski N, Kass D J. Micromanaging microRNAs: usingmurine models to study microRNAs in lung fibrosis [J]. Drug Discovery Today:Disease Models,2013.
[84] Fernandez I E, Eickelberg O. New cellular and molecular mechanisms of lung injuryand fibrosis in idiopathic pulmonary fibrosis[J]. The Lancet,2012,380(9842):680-688.
[1]Raghu G, Collard H R, Egan J J, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis andmanagement [J]. American Journal of Respiratory and Critical Care Medicine,2011,183(6):788-824.
[2]Navaratnam V, Fleming K M, West J, et al. The rising incidence of diopathicpulmonary fibrosis in the UK [J]. Thorax,2011,66(6):462-467.
[3]Li Z H, Peng S C, Kang J, et al. A retrospective cohort study of prognostic factors fordeath in patients with idiopathic pulmonary fibrosis [J]. Zhonghua jie he he hu xi za zhi,2010,33(12):887-891.
[4] Bando M, Hosono T, Mato N, et al. Long-term efficacy of inhaled N-acetylcysteine inpatients with idiopathic pulmonary fibrosis [J]. Internal Medicine,2010,49(21):2289-2296.
[5] Homma S, Azuma A, Taniguchi H, et al. Efficacy of inhaled N-acetylcysteinemonotherapy in patients with early stage idiopathic pulmonary fibrosis [J]. Respirology,2012,17(3):467-477.
[6] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis[J]. European Respiratory Journal,2010,35(4):821-829.
[7] Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone andprednisolone: different effects on pulmonary cytokines and growth factors inbleomycin-induced murine pulmonary fibrosis [J]. European journal of pharmacology,2008,590(1-3):400-408.
[8] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis[J]. European Respiratory Journal,2010,35(4):821-829.
[9] Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathicpulmonary fibrosis [J]. Cochrane Database Syst Rev,2010,9.
[10] Bussone G, Mouthon L. Interstitial lung disease in systemic sclerosis [J].Autoimmunity reviews,2011,10(5):248-255.
[11] Kameda H.[Imatinib][J]. Nihon Rinsho Men'eki Gakkai kaishi=Japanese journal ofclinical immunology,2009,32(2):77.
[12] Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonaryfibrosis:randomized placebo-controlled results[J].Am J Respir Crit CareMed,2010,181(6):604-610.
[13] Hilberg F, Roth G J, Krssak M, et al. BIBF1120: triple angiokinase inhibitor withsustained receptor blockade and good antitumor efficacy [J]. Cancer Research,2008,68(12):4774-4782.
[14] Gomer R H, Lupher Jr M L. Investigational approaches to therapies for idiopathicpulmonary fibrosis [J]. Expert opinion on investigational drugs,2010,19(6):737-745.
[15] Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor inidiopathic pulmonary fibrosis[J]. New England Journal of Medicine,2011,365(12):1079-1087.
[16] Higashiyama H, Yoshimoto D, Kaise T, et al. Inhibition of activin receptor-likekinase5attenuates bleomycin-induced pulmonary fibrosis [J]. Experimental andmolecular pathology,2007,83(1):39-46.
[17] Richter A, Puddicombe S M, Lordan J L, et al. The contribution of interleukin (IL)-4and IL-13to the epithelial-mesenchymal trophic unit in asthma [J]. American journalof respiratory cell and molecular biology,2001,25(3):385.
[18] Adamali H I, Maher T M. Current and novel drug therapies for idiopathic pulmonaryfibrosis [J]. Drug Design, Development and Therapy,2012,6:261-272.
[19] Moore B B, Kolodsick J E, Thannickal V J, et al. CCR2-mediated recruitment offibrocytes to the alveolar space after fibrotic injury[J]. The American journal ofpathology,2005,166(3):675-684.
[20] Baran C P, Opalek J M, McMaken S, et al. Important roles for macrophagecolony-stimulating factor, CC chemokine ligand2, and mononuclear phagocytes in thepathogenesis of pulmonary fibrosis[J]. American journal of respiratory and critical caremedicine,2007,176(1):78-89.
[21] Moore B B, Paine III R, Christensen P J, et al. Protection from pulmonary fibrosis inthe absence of CCR2signaling[J]. The Journal of Immunology,2001,167(8):4368-4377.
[22] Gharaee-Kermani M, McCullumsmith R E, Charo I F, et al. CC-chemokine receptor2required for bleomycin-induced pulmonary fibrosis[J]. Cytokine,2003,24(6):266-276.
[23] Girgis R E, Mathai S C. Pulmonary hypertension associated with chronic respiratorydisease [J]. Clinics in chest medicine,2007,28(1):219-232.
[24] Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary rehabilitation inpatients with idiopathic pulmonary fibrosis[J]. Respirology,2007,13(3):394-399.
[25] Trulock E P, Christie J D, Edwards L B, et al. Registry of the International Society forHeart and Lung Transplantation: twenty-fourth official adult lung and heart-lungtransplantation report-2007[J]. The Journal of heart and lung transplantation: theofficial publication of the International Society for Heart Transplantation,2007,26(8):782.
[26] Stehlik J, Edwards L B, Kucheryavaya A Y, et al. The registry of the InternationalSociety for Heart and Lung Transplantation: twenty-eighth adult heart transplantreport-2011[J]. Journal of Heart and Lung Transplantation,2011,30(10):1078.
[27] Raghu G, Freudenberger T D, Yang S, et al. High prevalence of abnormal acidgastro-oesophageal reflux in idiopathic pulmonary fibrosis[J]. European RespiratoryJournal,2006,27(1):136-142.
[28] Amigoni M, Bellani G, Scanziani M, et al. Lung injury and recovery in a murinemodel of unilateral acid aspiration: functional, biochemical, and morphologiccharacterization[J]. Anesthesiology,2008,108(6):1037-1046.
[29] Kwan M, Xu Y D, Raghu G, et al. Acid treatment of normal rat lungs releasestransforming growth factor-beta1(TGF-beta1) and increases connective tissuesynthesis[J]. Proceedings of the American Thoracic Society (PATS). Am J Respir CritCare Med,2007,175:967.
[30] Raghu G, Freudenberger T D, Yang S, et al. High prevalence of abnormal acidgastro-oesophageal reflux in idiopathic pulmonary fibrosis [J]. European RespiratoryJournal,2006,27(1):136-142.
[31]Zisman D A, Schwarz M, Anstrom K J, et al. A controlled trial of sildenafil inadvanced idiopathic pulmonary fibrosis[J]. The New England journal of medicine,2010,363(7):620.
[2]Fernandez I E, Eickelberg O. New cellular and molecular mechanisms of lung injuryand fibrosis in idiopathic pulmonary fibrosis[J]. The Lancet,2012,380(9842):680-688.
[3]Richeldi L, Davies H R, Ferrara G, et al. Corticosteroids for idiopathic pulmonaryfibrosis [J]. Cochrane Database Syst Rev,2003,3.
[4]Luppi F, Cerri S, Beghe B, et al. Corticosteroid and immunomodulatory agents inidiopathic pulmonary fibrosis[J]. Respiratory medicine,2004,98(11):1035-1044.
[5]Scotton C J, Chambers R C. Molecular Targets in Pulmonary FibrosisTheMyofibroblast in Focus [J]. CHEST Journal,2007,132(4):1311-1321.
[6]Bringardner B D, Baran C P, Eubank T D, et al. The role of inflammation in thepathogenesis of idiopathic pulmonary fibrosis [J]. Antioxidants&redox signaling,2008,10(2):287.
[7]Papaharalambus C A, Griendling K K. Basic mechanisms of oxidative stress andreactive oxygen species in cardiovascular injury [J]. Trends in cardiovascular medicine,2007,17(2):48-54.
[8]Wadsworth R M. Oxidative stress and the endothelium [J]. Experimental Physiology,2008,93(1):155-157.
[9]Kliment C R, Englert J M, Gochuico B R, et al. Oxidative stress alters syndecan-1distribution in lungs with pulmonary fibrosis [J]. Journal of Biological Chemistry,2009,284(6):3537-3545.
[10] Wynn T A. Integrating mechanisms of pulmonary fibrosis [J]. The Journal ofExperimental Medicine,2011,208(7):1339-1350.
[11] Morrisey E E. Wnt signaling and pulmonary fibrosis [J]. The American journal ofpathology,2003,162(5):1393.
[12] Fitch P M, Wakelin S J, Lowrey J A, et al. Shh expression in pulmonary injury anddisease[J]. Hedgehog-Gli Signaling in Human Disease,2006:119-128.
[13] Aoyagi-Ikeda K, Maeno T, Matsui H, et al. Notch induces myofibroblastdifferentiation of alveolar epithelial cells via transforming growth factor-{beta}-Smad3pathway[J]. American journal of respiratory cell and molecular biology,2011,45(1):136.
[14]Crosby L M, Waters C M. Epithelial repair mechanisms in the lung [J]. AmericanJournal of Physiology-Lung Cellular and Molecular Physiology,2010,298(6):715-731.
[15] Selman M, King T E, Pardo A. Idiopathic pulmonary fibrosis: prevailing and evolvinghypotheses about its pathogenesis and implications for therapy[J]. Annals of InternalMedicine,2001,134(2):136-151.
[16] Willis B C, Borok Z. TGF-β-induced EMT: mechanisms and implications for fibroticlung disease [J]. American Journal of Physiology-Lung Cellular and MolecularPhysiology,2007,293(3): L525-L534.
[17]Hashimoto N, Phan S H, Imaizumi K, et al. Endothelial–mesenchymal transition inbleomycin-induced pulmonary fibrosis [J]. American journal of respiratory cell andmolecular biology,2010,43(2):161.
[18] Wynn T A, Ramalingam T R. Mechanisms of fibrosis: therapeutic translation forfibrotic disease [J]. Nature medicine,2012,18(7):1028-1040.
[19] Jones M G. Triple therapy for idiopathic pulmonary fibrosis[J]. Thorax,2012.
[20]Raghu G, Anstrom K J, King Jr T E, et al. Prednisone, azathioprine, andN-acetylcysteine for pulmonary fibrosis[J]. The New England journal of medicine,2012,366(21):1968.
[21]Park S, Lee E J. Recent Advances in Idiopathic Pulmonary Fibrosis[J]. Tuberculosisand respiratory diseases,2013,74(1):1-6.
[22] Karihaloo A. Anti-Fibrosis Therapy and Diabetic Nephropathy [J]. Current DiabetesReports,2012:1-9.
[23]Potts J, Yogaratnam D. Pirfenidone: A Novel Agent for the Treatment of IdiopathicPulmonary Fibrosis[J]. The Annals of pharmacotherapy,2013,47(3):361-367.
[24] Raghu G, Collard H R, Egan J J, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis andmanagement [J]. American Journal of Respiratory and Critical Care Medicine,2011,183(6):788-824.
[25] Salhi B, Troosters T, Behaegel M, et al. Effects of pulmonary rehabilitation in patientswith restrictive lung diseases [J]. CHEST Journal,2010,137(2):273-279.
[26] Fang A, Studer S, Kawut S M, et al. Elevated pulmonary artery pressure is a riskfactor for primary graft dysfunction following lung transplantation for idiopathicpulmonary fibrosis[J]. CHEST Journal,2011,139(4):782-787.
[27] Lota H K, Wells A U. The evolving pharmacotherapy of pulmonary fibrosis [J].Expert opinion on pharmacotherapy,2013,14(1):79-89.
[28] Hogaboam C, Kunkel S L, Trujillo G. Biomakers predictive of progression of fibrosis:U.S. Patent20,120,282,276[P].2012-11-8.
[29] Aggarwal B B, Ichikawa H. Molecular targets and anticancer potential ofindole-3-carbinol and its derivatives [J].Cell Cycle,2005,4(9):1201-1215．
[30] Shimamoto K, Hayashi H, Taniai E, et al. Antioxidant N-acetyl-L-cysteine (NAC)supplementation reduces reactive oxygen species (ROS)-mediated hepatocellular tumorpromotion of indole-3-carbinol (I3C) in rats[J]. The Journal of toxicological sciences,2011,36(6):775-786.
[31] Shen A, Zhang B, Ping J, et al. In vivo study on the protection of indole-3-carbinol(I3C) against the mouse acute alcoholic liver injury by micro-Raman spectroscopy [J].Journal of Raman Spectroscopy,2009,40(5):550-555.
[32] Guo Y, Wu X Q, Zhang C, et al. Effect of indole-3-carbinol on ethanol-induced liverinjury and acetaldehyde-stimulated hepatic stellate cells activation using precision-cutrat liver slices [J]. Clinical and Experimental Pharmacology and Physiology,2010,37(12):1107-1113.
[33] Ping J, Li J, Liao Z, et al. Indole-3-carbinol inhibits hepatic stellate cells proliferationby blocking NADPH oxidase/reactive oxygen species/p38MAPK pathway [J].European journal of pharmacology,2011,650(2):656-662.
[34]Gao A M, Ping J, Wang H. Therapeutic effects of indole-3-carbinol on multiplehepatotoxic factors-induced liver fibrosis in rats [J]. Chinese Pharmacological Bulletin,2011,27(6):764-769.
[35]Ping J, Gao A M, Xu D, et al. Therapeutic effect of indole-3-carbinol on pigserum-induced hepatic fibrosis in rats [J]. Acta Pharmaceutica Sinica2011,46(8):915-921
[36] Szapiel S V, Elson N A, Fulmer J D, et al. Bleomycin-induced interstitial pulmonarydisease in the nude, athymic mouse[J]. The American review of respiratory disease,1979,120(4):893.
[37] Hubner RH, Gitter W, El MN, et al. Standardized quantification of pulmonary fibrosisin histological samples[J].Biotechniques,2008,44(4):507-511,514-517.
[38] Sriram N, Kalayarasan, Sudhandiran G. Enhancement of antioxidant defense systemby epigallocatechin-3-gallate during bleomycin induced experimental pulmonaryfibrosis [J]. Biol Pharm Bull,2008,31(7):1306-1311.
[39] Lacerda A C R, Rodrigues-Machado M G, Mendes P L, et al. Paraquat (PQ)-inducedpulmonary fibrosis increases exercise metabolic cost, reducing aerobic performance inrats[J]. The Journal of toxicological sciences,2009,34(6):671-679.
[40] Nagatani Y, Nitta N, Otani H, et al. Quantitative Measurement of Bleomycin inducedLung Fibrosis in Rabbits Using Sequential in vivo Regional Analysis andHigh-Resolution Computed Tomography:Correlation with Pathologic Findings[J].Academic Radiology,2011,18(6):672-681.
[41] Rashidi I, Mozaffari A R. Bleomycin Induced Pulmonary Fibrosis [J]. MJIRC,2005,7(3).
[42] Liu R, Ahmed K M, Nantajit D, et al. Therapeutic effects of alpha-lipoic acid onbleomycin-induced pulmonary fibrosis in rats[J]. International journal of molecularmedicine,2007,19(6):865.
[43] Li Guangming, Lei Jianping, Zeng Jianer. Inflammation cells, cytokines andpulmonary fibrosis in Bronchoalveolar lavage fluid[J]. Journal of Jianxi medicine,2010,45(12):1251-1253.
[44] Kolb M, Margetts P J, Anthony D C, et al. Transient expression of IL-1beta inducesacute lung injury and chronic repair leading to pulmonary fibrosis[J]. Journal ofClinical Investigation,2001,107(12):1529-1544.
[45] Uyttenhove C, Van Snick J. Development of an anti-IL-17A auto-vaccine thatprevents experimental auto-immune encephalomyelitis [J].European journal ofimmunology,2006,36(11).
[46] Crosby L M, Waters C M. Epithelial repair mechanisms in the lung[J]. AmericanJournal of Physiology-Lung Cellular and Molecular Physiology,2010,298(6):715-731.
[47] Nakerakanti S, Trojanowska M. Suppl1: The Role of TGF-β Receptors in Fibrosis[J].The Open Rheumatology Journal,2012,6:156.
[48] Thannickal V J, Horowitz J C. Evolving concepts of apoptosis in idiopathicpulmonary fibrosis[J]. Proceedings of the American Thoracic Society,2006,3(4):350-356.
[49] Guéders M, Foidart J M, Noel A, et al. Matrix metalloproteinases (MMPs) and tissueinhibitors of MMPs in the respiratory tract: potential implications in asthma and otherlung diseases[J]. European journal of pharmacology,2006,533(1-3):133-144.
[50] Kinnula V L, Fattman C L, Tan R J, et al. Oxidative Stress in Pulmonary Fibrosis APossible Role for Redox Modulatory Therapy[J]. American journal of respiratory andcritical care medicine,2005,172(4):417-422.
[51]Pan J, Su Y, Hou X, et al. Protective effect of recombinant protein SOD-TAT onradiation-induced lung injury in mice [J]. Life Sciences,2012.
[52]Xu H, Hao Y, Su Y, et al. Effect of Soyasaponin on Expression of Fas/FasL ofPneumonocyte in Silicotic Fibrosis Rats[M].Informatics and Management Science I.Springer London,2013:309-313.
[53] Pittet J F, Griffiths M J D, Geiser T, et al. TGF-beta is a critical mediator of acute lunginjury[J]. Journal of Clinical Investigation,2001,107(12):1537-1562.
[54] Challen G A, Boles N C, Chambers S M, et al. Distinct hematopoietic stem cellsubtypes are differentially regulated by TGF-β1[J]. Cell Stem Cell,2010,6(3):265-278.
[55] Qu L, Liu A, Zhou L, et al. Clinical and molecular effects on mature burn scars aftertreatment with a fractional CO2laser [J]. Lasers in Surgery and Medicine,2012.
[56] Usuki J,Matsuda K,Azuma A, et al. Sequential analysis of myofibroblastdifferentiation and transforming growth factor-beta1/Smad pathway activation inmurine pulmonary fibrosis[J].J Nihon Med Sch,2012,79(1):46-59.
[57] Willis BC, Borok Z. TGF-beta-induced EMT: mechanisms and implications forfibrotic lung disease [J].Am J Physiol Lung Cell Mol Physiol,2007,293(3):525-534.
[58] Ma R L, Wang W P, Jiang X G, et al. Effects of total flavonoids of scutellariabaicalensis georgi(TFSB) on bleomycin-induced pulmonary fibrosis in rats[J].ChinesePharmacological Bulletin,2011,27(4):537-542.
[59] Sobral L M, Montan P F, Zecchin K G, et al. Smad7Blocks Transforming GrowthFactor-β1–Induced Gingival Fibroblast–Myofibroblast Transition via InhibitoryRegulation of Smad2and Connective Tissue Growth Factor[J]. Journal ofPeriodontology,2011,82(4):642-651.
[60]Shivshankar P, Brampton C, Miyasato S, et al. Caveolin-1deficiency protects frompulmonary fibrosis by modulating epithelial cell senescence in mice[J]. Am J RespirCell Mol Biol,2012,47(1):28-36.
[61]Ghosh A K, Vaughan D E. PAI-1in tissue fibrosis[J]. Journal of cellular physiology,2012,227(2):493-507.
[62]King T E, Pardo A, Selman M. Idiopathic pulmonary fibrosis[J]. The Lancet,2011,378(9807):1949-1961.
[63] Tourkina E, Richard M, G z P, et al. Antifibrotic properties of caveolin-1scaffolding domain in vitro and in vivo[J]. American Journal of Physiology-LungCellular and Molecular Physiology,2008,294(5):843-861.
[64] Razani B, Zhang X L, Bitzer M, et al. Caveolin-1regulates transforming growthfactor (TGF)-β/SMAD signaling through an interaction with the TGF-β type Ireceptor[J]. Journal of Biological Chemistry,2001,276(9):6727-6738.
[65] Lee E K, Lee Y S, Han I O, et al. Expression of Caveolin-1reduces cellular responsesto TGF-β1through down-regulating the expression of TGF-β type II receptor gene inNIH3T3fibroblast cells[J]. Biochemical and biophysical research communications,2007,359(2):385-390
[66] Tuschl T, Lagos-quintana M, Lendeckel W, et al. MicroRNA molecules: EuropeanPatent EP2428571[P].2012-3-14.
[67]J Jiang X, Tsitsiou E, Herrick S E, et al. MicroRNAs and the regulation of fibrosis[J].FEBS Journal,2010,277(9):2015-2021.
[68]Yang I V. Epigenomics of idiopathic pulmonary fibrosis[J]. Epigenomics,2012,4(2):195-203.
[69] Frankel L B, Christoffersen N R, Jacobsen A, et al. Programmed cell death4(PDCD4)is an important functional target of the microRNA miR-21in breast cancer cells[J].Journal of Biological Chemistry,2008,283(2):1026-1033.
[70]Meng F, Henson R, Wehbe-Janek H, et al. MicroRNA-21regulates expression of thePTEN tumor suppressor gene in human hepatocellular cancer[J]. Gastroenterology,2007,133(2):647.
[71]Parasramka M A, Ho E, Williams D E, et al. MicroRNAs, diet, and cancer: newmechanistic insights on the epigenetic actions of phytochemicals[J]. Molecularcarcinogenesis,2011,51(3):213-230.
[72] Roy S, Khanna S, Hussain S R A, et al. MicroRNA expression in response to murinemyocardial infarction: miR-21regulates fibroblast metalloprotease-2via phosphataseand tensin homologue[J]. Cardiovascular research,2009,82(1):21-29.
[73] Bauersachs J. miR-21: a central regulator of fibrosis not only in the broken heart[J].Cardiovascular Research,2012
[74]Liu G, Friggeri A, Yang Y, et al. miR-21mediates fibrogenic activation of pulmonaryfibroblasts and lung fibrosis[J]. The Journal of experimental medicine,2010,207(8):1589-1597.
[75]Thum T, Gross C, Fiedler J, et al. MicroRNA-21contributes to myocardial disease bystimulating MAP kinase signalling in fibroblasts[J]. Nature,2008,456(7224):980-984.
[76]Bhagat T D, Zhou L, Sokol L, et al. miR-21mediates hematopoietic suppression inMDS by activating TGF-β signaling [J]. Blood,2013.
[77] Liu G, Friggeri A, Yang Y, et al. miR-21mediates fibrogenic activation of pulmonaryfibroblasts and lung fibrosis[J]. The Journal of experimental medicine,2010,207(8):1589-1597.
[78]Wang Y, Hu X, Greshock J, et al. Genomic DNA Copy-Number Alterations of thelet-7Family in Human Cancers[J]. PloS one,2012,7(9): e44399.
[79]Rabinovich E I, Selman M, Kaminski N. Epigenomics of Idiopathic PulmonaryFibrosis Evaluating the First Steps[J]. American Journal of Respiratory and CriticalCare Medicine,2012,186(6):473-475.
[80] Pandit K V, Corcoran D, Yousef H, et al. Inhibition and role of let-7d in idiopathicpulmonary fibrosis[J]. American journal of respiratory and critical care medicine,2010,182(2):220-229.
[81] Blahna M T, Hata A. Smad-mediated regulation of microRNA biosynthesis[J]. FEBSletters,2012,586(14):1906-1912.
[82] Peter M E. Let-7and miR-200microRNAs: guardians against pluripotency and cancerprogression[J]. Cell Cycle,2009,8(6):843-852.
[83] Lino Cardenas C L, Kaminski N, Kass D J. Micromanaging microRNAs: usingmurine models to study microRNAs in lung fibrosis [J]. Drug Discovery Today:Disease Models,2013.
[84] Fernandez I E, Eickelberg O. New cellular and molecular mechanisms of lung injuryand fibrosis in idiopathic pulmonary fibrosis[J]. The Lancet,2012,380(9842):680-688.
[1]Raghu G, Collard H R, Egan J J, et al. An official ATS/ERS/JRS/ALAT statement:idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis andmanagement [J]. American Journal of Respiratory and Critical Care Medicine,2011,183(6):788-824.
[2]Navaratnam V, Fleming K M, West J, et al. The rising incidence of diopathicpulmonary fibrosis in the UK [J]. Thorax,2011,66(6):462-467.
[3]Li Z H, Peng S C, Kang J, et al. A retrospective cohort study of prognostic factors fordeath in patients with idiopathic pulmonary fibrosis [J]. Zhonghua jie he he hu xi za zhi,2010,33(12):887-891.
[4] Bando M, Hosono T, Mato N, et al. Long-term efficacy of inhaled N-acetylcysteine inpatients with idiopathic pulmonary fibrosis [J]. Internal Medicine,2010,49(21):2289-2296.
[5] Homma S, Azuma A, Taniguchi H, et al. Efficacy of inhaled N-acetylcysteinemonotherapy in patients with early stage idiopathic pulmonary fibrosis [J]. Respirology,2012,17(3):467-477.
[6] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis[J]. European Respiratory Journal,2010,35(4):821-829.
[7] Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone andprednisolone: different effects on pulmonary cytokines and growth factors inbleomycin-induced murine pulmonary fibrosis [J]. European journal of pharmacology,2008,590(1-3):400-408.
[8] Taniguchi H, Ebina M, Kondoh Y, et al. Pirfenidone in idiopathic pulmonary fibrosis[J]. European Respiratory Journal,2010,35(4):821-829.
[9] Spagnolo P, Del Giovane C, Luppi F, et al. Non-steroid agents for idiopathicpulmonary fibrosis [J]. Cochrane Database Syst Rev,2010,9.
[10] Bussone G, Mouthon L. Interstitial lung disease in systemic sclerosis [J].Autoimmunity reviews,2011,10(5):248-255.
[11] Kameda H.[Imatinib][J]. Nihon Rinsho Men'eki Gakkai kaishi=Japanese journal ofclinical immunology,2009,32(2):77.
[12] Daniels CE, Lasky JA, Limper AH, et al. Imatinib treatment for idiopathic pulmonaryfibrosis:randomized placebo-controlled results[J].Am J Respir Crit CareMed,2010,181(6):604-610.
[13] Hilberg F, Roth G J, Krssak M, et al. BIBF1120: triple angiokinase inhibitor withsustained receptor blockade and good antitumor efficacy [J]. Cancer Research,2008,68(12):4774-4782.
[14] Gomer R H, Lupher Jr M L. Investigational approaches to therapies for idiopathicpulmonary fibrosis [J]. Expert opinion on investigational drugs,2010,19(6):737-745.
[15] Richeldi L, Costabel U, Selman M, et al. Efficacy of a tyrosine kinase inhibitor inidiopathic pulmonary fibrosis[J]. New England Journal of Medicine,2011,365(12):1079-1087.
[16] Higashiyama H, Yoshimoto D, Kaise T, et al. Inhibition of activin receptor-likekinase5attenuates bleomycin-induced pulmonary fibrosis [J]. Experimental andmolecular pathology,2007,83(1):39-46.
[17] Richter A, Puddicombe S M, Lordan J L, et al. The contribution of interleukin (IL)-4and IL-13to the epithelial-mesenchymal trophic unit in asthma [J]. American journalof respiratory cell and molecular biology,2001,25(3):385.
[18] Adamali H I, Maher T M. Current and novel drug therapies for idiopathic pulmonaryfibrosis [J]. Drug Design, Development and Therapy,2012,6:261-272.
[19] Moore B B, Kolodsick J E, Thannickal V J, et al. CCR2-mediated recruitment offibrocytes to the alveolar space after fibrotic injury[J]. The American journal ofpathology,2005,166(3):675-684.
[20] Baran C P, Opalek J M, McMaken S, et al. Important roles for macrophagecolony-stimulating factor, CC chemokine ligand2, and mononuclear phagocytes in thepathogenesis of pulmonary fibrosis[J]. American journal of respiratory and critical caremedicine,2007,176(1):78-89.
[21] Moore B B, Paine III R, Christensen P J, et al. Protection from pulmonary fibrosis inthe absence of CCR2signaling[J]. The Journal of Immunology,2001,167(8):4368-4377.
[22] Gharaee-Kermani M, McCullumsmith R E, Charo I F, et al. CC-chemokine receptor2required for bleomycin-induced pulmonary fibrosis[J]. Cytokine,2003,24(6):266-276.
[23] Girgis R E, Mathai S C. Pulmonary hypertension associated with chronic respiratorydisease [J]. Clinics in chest medicine,2007,28(1):219-232.
[24] Nishiyama O, Kondoh Y, Kimura T, et al. Effects of pulmonary rehabilitation inpatients with idiopathic pulmonary fibrosis[J]. Respirology,2007,13(3):394-399.
[25] Trulock E P, Christie J D, Edwards L B, et al. Registry of the International Society forHeart and Lung Transplantation: twenty-fourth official adult lung and heart-lungtransplantation report-2007[J]. The Journal of heart and lung transplantation: theofficial publication of the International Society for Heart Transplantation,2007,26(8):782.
[26] Stehlik J, Edwards L B, Kucheryavaya A Y, et al. The registry of the InternationalSociety for Heart and Lung Transplantation: twenty-eighth adult heart transplantreport-2011[J]. Journal of Heart and Lung Transplantation,2011,30(10):1078.
[27] Raghu G, Freudenberger T D, Yang S, et al. High prevalence of abnormal acidgastro-oesophageal reflux in idiopathic pulmonary fibrosis[J]. European RespiratoryJournal,2006,27(1):136-142.
[28] Amigoni M, Bellani G, Scanziani M, et al. Lung injury and recovery in a murinemodel of unilateral acid aspiration: functional, biochemical, and morphologiccharacterization[J]. Anesthesiology,2008,108(6):1037-1046.
[29] Kwan M, Xu Y D, Raghu G, et al. Acid treatment of normal rat lungs releasestransforming growth factor-beta1(TGF-beta1) and increases connective tissuesynthesis[J]. Proceedings of the American Thoracic Society (PATS). Am J Respir CritCare Med,2007,175:967.
[30] Raghu G, Freudenberger T D, Yang S, et al. High prevalence of abnormal acidgastro-oesophageal reflux in idiopathic pulmonary fibrosis [J]. European RespiratoryJournal,2006,27(1):136-142.
[31]Zisman D A, Schwarz M, Anstrom K J, et al. A controlled trial of sildenafil inadvanced idiopathic pulmonary fibrosis[J]. The New England journal of medicine,2010,363(7):620.