TGF-β_1/Smad信号通路在哮喘小鼠气道黏液高分泌中的作用
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摘要
第一部分哮喘小鼠气道黏液分泌的变化
目的观察哮喘小鼠气道炎症的表现,并证实哮喘小鼠气道黏液高分泌的存在。方法将20只清洁级BALB/c小鼠随机分为2组：哮喘组(OVA组)、对照组(NS组),每组10只。哮喘组用卵蛋白(OVA)致敏和激发制作哮喘模型,对照组用生理盐水致敏和激发。检测支气管肺泡灌洗液(BALF)中细胞总数和细胞分类计数,采用酶联免疫吸附试验(ELISA)检测BALF中的IL-4和肿瘤坏死因子-α(TNF-α)水平,用阿尔辛蓝—过碘酸雪夫氏染色(AB-PAS)气道杯状细胞、用免疫组织化学检测气道组织中Muc5ac蛋白的表达及实时荧光定量逆转录聚合酶(RT-PCR)检测Muc5ac mRNA在气道组织的表达。结果OVA组小鼠BALF中的细胞总数、淋巴细胞和嗜酸性粒细胞高于NS组小鼠(P均<0.01),BALF中IL-4和TNF-α水平、气道杯状细胞阳性着色面积及气道组织中Muc5ac蛋白及其mRNA较NS组升高(P均<0.01)。结论哮喘小鼠存在气道炎症及气道黏液高分泌。
第二部分TGF-β1/Smad信号通路在哮喘小鼠气道黏液高分泌中的作用及吡非尼酮的干预影响
目的观察TGF-β1/Smad信号通路在支气管哮喘小鼠气道黏液高分泌中的作用。
方法清洁级BALB/c小鼠40只,随机分为5组：正常对照组(NS组)8只,哮喘组(OVA组)8只,地塞米松干预组(OVA+DEX组)8只,溶剂对照组(OVA+SJ组)8只,吡非尼酮干预组(OVA+PFD组)8只。测定BALF中细胞总数和细胞分类计数,采用酶联免疫吸附试验(ELISA)检测BALF中的IL-4和TNF-a水平,用阿尔辛蓝—过碘酸雪夫氏染色(AB-PAS)对气道杯状细胞进行染色,用免疫组织化学法检测气道组织Muc5ac和肺组织TGF-βl的表达及实时荧光定量逆转录聚合酶(RT-PCR)检测Muc5ac mRNA、TGF-β1mRNA、Smad3及Smad4在肺组织内的表达。结果OVA组在BALF细胞总数、嗜酸性粒细胞数及气道杯状细胞阳染面积及免疫组化黏蛋白Muc5ac、转化生长因子TGF-β1积分光密度值及肺组织Muc5ac mRNA、TGF-p1mRNA、Smad3 mRNA、Smad4 mRNA表达与OVA+PFD组、NS组比较差异有统计学意义(P均<0.01), OVA组在BALF细胞总数、嗜酸性粒细胞数及AB-PAS阳染面积及免疫组化黏蛋白Muc5ac与OVA+DEX组比较差异有统计学意义(P均<0.01),但肺组织TGF-p1积分光密度值及TGF-β1 mRNA、Smad3 mRNA、Smad4 mRNA的表达水平两组无差异性(P>0.05)。OVA+PFD组小鼠气道杯状细胞及气道组织中的Muc5ac蛋白和TGF-β1及Muc5ac mRNA、TGF-β1 mRNA, Smad3 mRNA、Smad4 mRNA低于OVA+DEX组(P均＜0.01)。OVA组和OVA+SJ组在上述指标则组间差异无统计学意义(P>0.05)。结论哮喘小鼠肺组织TGF-β1蛋白、Smad3、Smad4蛋白及其mRNA和气道组织Muc5ac蛋白及其mRNA均成高表达改变。吡非尼酮可以抑制肺组织TGF-β1及Smad蛋白的表达,下调气道组织黏蛋白Muc5ac的表达,提示TGF-β1/Smad信号通路在气道黏液高分泌中发挥作用。
Part 1 The airway mucus hypersecretion in asthmatic mice
Objective To investigate airway inflammation in asthmatic mice, and confirm that asthmatic mice have mucus hypersecretion. Method Twenty clean BALB/c rats were randomly divided into two groups:control group asthmatic model group(OVA group, n=10), (NS group, n=10). asthmatic model group made asthmatic model in sensitized and challenged with ovalbumin (OVA), control group was sensitized and challenged with normal sodium. After three weeks, total cells and differential inflammatory cells were counted in bronchoalveolar lavage fluid (BALF), the levels IL-4 and TNF-a in BALF were determined by enzyme-linked immuno sorbent assay (ELISA), positive staining in the area of the goblet cell in airway wall was observed by a first blue-periodic acid Schiff reagent staining (AB-PAS), the expression of Muc5ac in airway were observed by immunohistochemical staining, the expressions of Muc5ac mRNA in airway tissue were observed real-time quantitative reverse transcription polymerase reaction (RT-PCR). Result Total cells, lymphocyte and eosinophil cells in BALF of athmatic model group were obviously higher than control group(P<0.01); the levels of IL-4 and TNF-a in BALF, positive staining in the area of the goblet cell in airway wall, and Muc5ac in the protein and gene level were higher than those in control group(P<0.01). Conclusion asthmatic mice have apparente inflammatory cell infiltration, and secrete a great quantity mucosubstance.
Pary 2 The effect of TGF-β1/Smad signaling pathways in airway
mucus hypersecretion of asthmatic mice treated with pirfenidone Objective To investigate the effect of TGF-β1/Smad signaling pathways on mucus of hypersecretion asthmatic mice treated with pirfenidone.Methods Forty clean BALB/c rats were randomly divided into five groups:control group (NS group, n=8), asthmatic model group(OVA group, n=8), dexamethasone (DEX) treatment group(OVA+DEX group, n=8)),pirfenidone (PFD) treatment group (OVA+PFD group, n=8), Solvent control group (OVA+SJ group,n=8).Total cells and differential inflammatory cells were counted in bronchoalveolar lavage fluid (BALF), the levels of IL-4 and TNF-a in BALF were determined by enzyme-linked immuno sorbent assay (ELISA), positive staining in the area of the goblet cell in airway wall was observed by alcian blue/periodic acid schiff staining (AB-PAS), the expressions of Muc5ac in airway tissue and TGF-β1 in lung tissue were observed by immuneohistochemical staining, the expressions of Muc5acmRNA and TGF-β1mRNA and Smad3 mRNA and Smad4 mRNA in lung tissue were observed by real-time quantitative reverse transcription polymerase reaction (RT-PCR).Result Total cells、eosinophil cells and lymphocyte cells in BALF, the levels of IL-4 and TNF-a in BALF, positive staining in the area of the goblet cell in airway wall, and the expression of Muc5ac in the protein and gene level of OVA group were obviously higher than those in control group and (OVA+PFD) group (P<0.01), TGF-β1, Smad3 and Smad4 in the protein and gene level were higher than those in control group and (OVA+PFD) group (P<0.01), while were Non-significance difference Between OVA group and (OVA+DEX) control group(P>0.05).Conclusion The expressions of TGF-β1、Smad3 and Smad4 in the protein and gene level in lung tissue were higher than those in control group,and Muc5ac in the protein and gene level in airway tissue were higher than those in control group(P<0.01) PFD may inhibit the expressions of TGF-β1、Smad3 and Smad4 in the protein and gene level in lung tissue, and down the expressions of Muc5ac in the protein and gene level in airway tissue, illustrating TGF-β1/Smad signal pathway play a role in airway mucus hypersecretion.
目的观察哮喘小鼠气道炎症的表现,并证实哮喘小鼠气道黏液高分泌的存在。方法将20只清洁级BALB/c小鼠随机分为2组：哮喘组(OVA组)、对照组(NS组),每组10只。哮喘组用卵蛋白(OVA)致敏和激发制作哮喘模型,对照组用生理盐水致敏和激发。检测支气管肺泡灌洗液(BALF)中细胞总数和细胞分类计数,采用酶联免疫吸附试验(ELISA)检测BALF中的IL-4和肿瘤坏死因子-α(TNF-α)水平,用阿尔辛蓝—过碘酸雪夫氏染色(AB-PAS)气道杯状细胞、用免疫组织化学检测气道组织中Muc5ac蛋白的表达及实时荧光定量逆转录聚合酶(RT-PCR)检测Muc5ac mRNA在气道组织的表达。结果OVA组小鼠BALF中的细胞总数、淋巴细胞和嗜酸性粒细胞高于NS组小鼠(P均<0.01),BALF中IL-4和TNF-α水平、气道杯状细胞阳性着色面积及气道组织中Muc5ac蛋白及其mRNA较NS组升高(P均<0.01)。结论哮喘小鼠存在气道炎症及气道黏液高分泌。
第二部分TGF-β1/Smad信号通路在哮喘小鼠气道黏液高分泌中的作用及吡非尼酮的干预影响
目的观察TGF-β1/Smad信号通路在支气管哮喘小鼠气道黏液高分泌中的作用。
方法清洁级BALB/c小鼠40只,随机分为5组：正常对照组(NS组)8只,哮喘组(OVA组)8只,地塞米松干预组(OVA+DEX组)8只,溶剂对照组(OVA+SJ组)8只,吡非尼酮干预组(OVA+PFD组)8只。测定BALF中细胞总数和细胞分类计数,采用酶联免疫吸附试验(ELISA)检测BALF中的IL-4和TNF-a水平,用阿尔辛蓝—过碘酸雪夫氏染色(AB-PAS)对气道杯状细胞进行染色,用免疫组织化学法检测气道组织Muc5ac和肺组织TGF-βl的表达及实时荧光定量逆转录聚合酶(RT-PCR)检测Muc5ac mRNA、TGF-β1mRNA、Smad3及Smad4在肺组织内的表达。结果OVA组在BALF细胞总数、嗜酸性粒细胞数及气道杯状细胞阳染面积及免疫组化黏蛋白Muc5ac、转化生长因子TGF-β1积分光密度值及肺组织Muc5ac mRNA、TGF-p1mRNA、Smad3 mRNA、Smad4 mRNA表达与OVA+PFD组、NS组比较差异有统计学意义(P均<0.01), OVA组在BALF细胞总数、嗜酸性粒细胞数及AB-PAS阳染面积及免疫组化黏蛋白Muc5ac与OVA+DEX组比较差异有统计学意义(P均<0.01),但肺组织TGF-p1积分光密度值及TGF-β1 mRNA、Smad3 mRNA、Smad4 mRNA的表达水平两组无差异性(P>0.05)。OVA+PFD组小鼠气道杯状细胞及气道组织中的Muc5ac蛋白和TGF-β1及Muc5ac mRNA、TGF-β1 mRNA, Smad3 mRNA、Smad4 mRNA低于OVA+DEX组(P均＜0.01)。OVA组和OVA+SJ组在上述指标则组间差异无统计学意义(P>0.05)。结论哮喘小鼠肺组织TGF-β1蛋白、Smad3、Smad4蛋白及其mRNA和气道组织Muc5ac蛋白及其mRNA均成高表达改变。吡非尼酮可以抑制肺组织TGF-β1及Smad蛋白的表达,下调气道组织黏蛋白Muc5ac的表达,提示TGF-β1/Smad信号通路在气道黏液高分泌中发挥作用。
Part 1 The airway mucus hypersecretion in asthmatic mice
Objective To investigate airway inflammation in asthmatic mice, and confirm that asthmatic mice have mucus hypersecretion. Method Twenty clean BALB/c rats were randomly divided into two groups:control group asthmatic model group(OVA group, n=10), (NS group, n=10). asthmatic model group made asthmatic model in sensitized and challenged with ovalbumin (OVA), control group was sensitized and challenged with normal sodium. After three weeks, total cells and differential inflammatory cells were counted in bronchoalveolar lavage fluid (BALF), the levels IL-4 and TNF-a in BALF were determined by enzyme-linked immuno sorbent assay (ELISA), positive staining in the area of the goblet cell in airway wall was observed by a first blue-periodic acid Schiff reagent staining (AB-PAS), the expression of Muc5ac in airway were observed by immunohistochemical staining, the expressions of Muc5ac mRNA in airway tissue were observed real-time quantitative reverse transcription polymerase reaction (RT-PCR). Result Total cells, lymphocyte and eosinophil cells in BALF of athmatic model group were obviously higher than control group(P<0.01); the levels of IL-4 and TNF-a in BALF, positive staining in the area of the goblet cell in airway wall, and Muc5ac in the protein and gene level were higher than those in control group(P<0.01). Conclusion asthmatic mice have apparente inflammatory cell infiltration, and secrete a great quantity mucosubstance.
Pary 2 The effect of TGF-β1/Smad signaling pathways in airway
mucus hypersecretion of asthmatic mice treated with pirfenidone Objective To investigate the effect of TGF-β1/Smad signaling pathways on mucus of hypersecretion asthmatic mice treated with pirfenidone.Methods Forty clean BALB/c rats were randomly divided into five groups:control group (NS group, n=8), asthmatic model group(OVA group, n=8), dexamethasone (DEX) treatment group(OVA+DEX group, n=8)),pirfenidone (PFD) treatment group (OVA+PFD group, n=8), Solvent control group (OVA+SJ group,n=8).Total cells and differential inflammatory cells were counted in bronchoalveolar lavage fluid (BALF), the levels of IL-4 and TNF-a in BALF were determined by enzyme-linked immuno sorbent assay (ELISA), positive staining in the area of the goblet cell in airway wall was observed by alcian blue/periodic acid schiff staining (AB-PAS), the expressions of Muc5ac in airway tissue and TGF-β1 in lung tissue were observed by immuneohistochemical staining, the expressions of Muc5acmRNA and TGF-β1mRNA and Smad3 mRNA and Smad4 mRNA in lung tissue were observed by real-time quantitative reverse transcription polymerase reaction (RT-PCR).Result Total cells、eosinophil cells and lymphocyte cells in BALF, the levels of IL-4 and TNF-a in BALF, positive staining in the area of the goblet cell in airway wall, and the expression of Muc5ac in the protein and gene level of OVA group were obviously higher than those in control group and (OVA+PFD) group (P<0.01), TGF-β1, Smad3 and Smad4 in the protein and gene level were higher than those in control group and (OVA+PFD) group (P<0.01), while were Non-significance difference Between OVA group and (OVA+DEX) control group(P>0.05).Conclusion The expressions of TGF-β1、Smad3 and Smad4 in the protein and gene level in lung tissue were higher than those in control group,and Muc5ac in the protein and gene level in airway tissue were higher than those in control group(P<0.01) PFD may inhibit the expressions of TGF-β1、Smad3 and Smad4 in the protein and gene level in lung tissue, and down the expressions of Muc5ac in the protein and gene level in airway tissue, illustrating TGF-β1/Smad signal pathway play a role in airway mucus hypersecretion.
引文
1. Howell JE, McAnulty RJ. TGF-beta:its role in asthma and therapeutic potential. Curr Drug Targets,2006,7:547-565.
2. Liang YF,Zhang WX,Li XX, et al.Changes in urotensin-Ⅱ expression in airway remodelling in asthmatic rats. Zhong guo DangDaiErKeZaZhi,2010,12(4):287-9.
3. Hornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu RevPhysiol,2008,70:459-486.
4. Turner J, Jones CE.Regulation of mucin expression in respiratory diseases. Biochem Soc Trans,2009,37(4):877-81.
5. Rubin BK. Mucus and mucins. Otolaryngol Clin North Am,2010,43(1):27-34.
6. Makinde T, Murphy RF, Agrawal DK.The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol,2007,85(5):348-56.
7. Atamas SP,White B. Cytokine regulation of pulmonary fibrosis in scleroderma.Cytokine Growth Factor Rev,2003,14(6):537.
8. Chung SW, Miles FL, Sikes RA,et al. Quantitative modeling and analysis of the transforming growth factor beta signaling pathway. Biophys,2009,96(5):1733-50.
9. David C. Clarke, Xuedong Liu. Decoding the quantitative nature of TGF-β3/Smad signaling.Trends Cell Biol,2008,18(9):430-442.
10. Manuyakorn W, Kamchaisatian W, Atamasirikul K,et al. Serum TGF-betal in atopic asthma. Asian Pac J Allergy Immunol,2008,26(4):185-9.
11. Kenyon,N. J,R. W. Ward,et al. TGF-β1 causes airway fibrosis and increased collagen I and IIImRNA in mice. Thorax,2003,58:772.
12. Chen G, Khalil N. TGF-β1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respir Res,2006,7(1):2.
13. Sarah J,McMillan,Georgina Xanthou,et al. Manipulation of Allergen-Induced Airway Remodeling by Treatment with Anti-TGF-beta Antibody Effect on the Smad Signaling Pathway.The Journal of Immunology,2005,174:5774-5780.
14. Oku H, Shimizu T, Kawabata T,et al.Antifibrotic action of pirfenidone and prednisolone:different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol, 2008,590(1-3):400-8.
15. RamachandraRao SP, Zhu Y, Ravasi T,et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009,20(8):1765-75.
16. Di Sario A, Bendia E, Svegliati Baroni G,et al. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. J Hepatol,2002,37(5):584-591.
17. Tobin MJ. Asthma, airway biology, and nasal disorders in AJRCCM2001. Am J Respir Crit Care Med,2002,165:598-618.
18. Trautmann A,Schmid-Grendelmeier P, Kruger K, etal. T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy Clin Immuunol,2002,109:329-337.
19. WEN Xiu-fang, ZHOU Xiang-dong. Goblet cellsmetaplasia and secreting regulation of air way epithelium. International Journal of Pathology and Clinical Medicine,2008, 28(1):0059-05.
20.王莹,王华英,谢强敏,等.哮喘小鼠气道上皮杯状细胞增生模型.中国药理学通报,2006,22(22)：251-253.
21. Martinez-Anton A,Debolos C,Garrido M,et al. Mucin genes have different expression patterns in healthy and diseased upper airway mucosa. Clin Exp Allergy,2006,36(4): 448-457.
22. Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary isease:comparisons with asthma. JAllergy Clin Immunol,2003,112:819-827
23. Tillie-Leblond I,Gosset P, Tonnel AB.Inflammatory events in severe acute asthma.Allergy,2005,60:23-29.
24. Pabst R. Animal model for asthma:controversial aspects and unsolved problems.Pathobiology,2003,70(5):260-265.
25. Hayashi T,Adachi Y,Hasegawa K,et al.Less sensitivity for late airway inflammation in males than females in BALB/c mice.Scand J Immunol,2003,57(6):562.
26. Fuchs B, Braun A. Improved mouse models of allergy and allergic asthma-chances beyond ovalbumin. Curr Drug Targets,2008,9(6):495-502.
1. Tomasiak-Lozowska MM, Bodzenta-Lukaszyk A, Tomasiak M.et al. The role of interleukin 13 and interleukin 5 in asthma. Postepy Hig Med Dosw (Online), 2010,64:146-55.
2. Antoniu SA.Cytokine antagonists for the treatment of asthma:progress to date. BioDrugs,2009,23(4):241-51.
3. LI Ming-cai, HE Shao-heng. Role of transforming growth factor-β in the airway inflammation and remodeling in asthma. Chinese Journal of Pathophysiology,2004, 20(8):1527-1530.
4. Moore B, Murphy RF, Agrawal DK. Interaction of tgf-beta with immune cells in airway disease. Curr Mol Med,2008,8(5):427-36.
5. Mc-Millan SJ, Xanthou G, L loyd CM. Manipulat ion of Allergen-induced airway remodeling by treatment with anti-TGF-beta ant ibody:effect on the Smad signaling pathway. J Immunol,2005,174 (9):5774-5780.
6. L e AV, Cho JY,M illerM, et al. Inh ibit ion of allergen induced airw ay remodeling in Smad-3deficient mice. J Immuno 1,2007,178 (11):7310-7316.
7. Ro sendah 1 A, Checch in D, Fehniger TE, et al.Activation of the TGF-beta/act ivin-Smad-pathway during allergic airway inflammation. Am J Resp ir CellMo 1B io 1,2001,25(1):60-68.
8. Bataller R, Brenner D A. Liver fibrosis. J Clin Invest,2005,115(2):209-218.
9. Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir,2010, 35(4):728-9.
10. Mitani Y, Sato K, Muramoto Y, Karakawa T,et al. Superoxide scavenging activity of pirfenidone-iron complex. Biochem Biophys Res Commun,2008,372(1):19-23.
11. Mei S, Yao W, Zhu Y, et al. Protection of pirfenidone against an early phase of oleic acid-induced acute lung injury in rats. J Pharmacol Exp Ther,2005,313(1):379-388.
12. Murakami M, Kawachi H, Ogawa K, et al.Receptor expression modulates the specificity of transforming growth factor-beta signaling pathways. Genes Cells, 2009,14(4):469-82.
13. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, et al. TGF-beta signals through a heteromeric protein kinase receptor complex. Cell,1992,71:1003-1014.
14. Sekelsky J J,Newfeld S,Raftery L A,et al.Genetic characterization and cloning of Mothers against dpp,a gene required fordecapentaplegic function in Drosophila melanogaster. Genetics,1995,139:1347-1358.
15. Lin X, Chen Y, Meng A, Feng X.Termination of TGF-beta superfamily signaling through SMAD dephosphorylation--a functional genomic view. J Genet Genomics, 2007,34(1):1-9.
16. Bornstein S, White R, Malkoski S,et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. Clin Invest, 2009,119(11):3408-19.
17. Brown KA, Pietenpol JA, Moses HL.A tale of two proteins:differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem,2007, 101(1):9-33.
18. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signaling. nature,2003,425(6958):577.
19. WANG Li, HUO Yan-ying, ZHANG Kai-tai, et al. The Effect of Smad7 Gene on Nuclear Translocation of Smad2/3/4. LETTERS IN BIOTECHNOLOGY,2005, 16(2):128-130.
20. Lin HM, Lee JH, Yadav H.Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem,2009,284(18):12246-57.
21. CHENG Hong, SONG Enfeng. Effects of Eucommia on TGF-β1/ Smad Signaling Pathway in Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction. CJ ITWN,2009,10(6):502-504.
22. Zhou L, Fu P, Huang XR, et al. Mechanism of chronic aristolochic acid nephropathy: role of Smad3. Am J Physiol Renal Physiol,2010,298(4):F1006-17.
23. Schiffer M, von Gersdorff G, Bitzer M, et al. Smad proteins and transforming growth factor-beta signaling. Kidney Int Suppl,2000,77:S45-S52.
24. Wang LF, Zhang L, Zhang RY,et al. Relationship between expression of Smad and ventricular remodeling after myocardial infarction in rats. Zhonghua Xin Xue Guan Bing Za Zhi,2005,33(10):932-5.
25. Makinde T,M urphy RF,A grawal DK,et al. The regulatory role of TGF-beta in airway remodeling in asthma. Immuno 1 Cell Biol,2007,85(5):348-356.
26. Magnan A,Retornaz F,Tsicopoulos A,et al. Altered compartmentalization of transforming growth factor-beta in asthmatic airways. Clin Exp Allergy,1997,27: 389-395.
27. CHEN HengHua,SUN Jie,CHEN Qing-mei. Effects of Curcine on airway remodeling and TGF-β1 mRNA in asthmatic mice. J Fourth MilMed Univ,2009,30(11):989-992.
28. REDINGTON AE, MADDEN J, FREW AJ, et al. Transforming Growth Factor-β1 in Asthma Measurement in Broncho alveolar Lavage Fluid. Am J Respir Crit Care Med, 1997,156:642-647.
29. Shen ZJ, Esnault S, Rosenthal LA,et al. Pinl regulates TGF-betal production by-activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest,2008,118(2):479-90.
30. Liu JB, Zhang ZX, Xu YJ,et al.Effects of glucocorticoid on airway mucus secretion in asthma:experiment with asthmatic mouse model. Zhonghua Yi Xue Za Zhi,2006, 86(35):2491-4.
31. Komatsu K, Jono H, Lim JH,et al. Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK. Biochem Biophys Res Commun,2008,377(3):763-8.
32. LIU Ping-li, LV Li-li. Effects of Dexamethsone on proliferation of airway smooth muscle cells and transforming growth factor-β1 in chronic asthma mice. China Journal of Modern Medicine,2008,18(10):1353-1356.
1. Moore B, Murphy RF, Agrawal DK. Interaction of tgf-beta with immune cells in airway disease. Curr Mol Med,2008,8(5):427-36.
2. Hyvarinen MK, Kotaniemi-Syrjanen A, Reijonen TM, et al.Eosinophil activity in infants hospitalized for wheezing and risk of persistent childhood asthma. Pediatr Allergy Immunol,2010,21(11):96-103.
3. Wang HB, Ghiran I, Matthaei K, Weller PF. Airway eosinophils:allergic inflamm-ation recruited professional antigen-presenting cells. J Immunol,2007,179 (11): 7585-92.
4. Walsh ER, Stokes K, August A. The role of eosinophils in allergic airway inflammation. Discov Med,2010,9(47):357-62.
5. Yuksel B, Aydemir C, Ustundag G,et al. The effect of treatment with montelukast on levels of serum interleukin-10, eosinophil cationic protein, blood eosinophil counts, and clinical parameters in children with asthma. Turk J Pediatr,2009,51 (5):460-5.
6. Message SD, Laza-Stanca V, Mallia P,et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci USA,2008,105(36):13562-7.
7. Shin SM, Kim YH, Choi BK,et al.4-1BB triggers IL-13 production from T cells to limit the polarized, Thl-mediated inflammation. J Leukoc Biol,2007,81(6):1455-65.
8. Lemanske RF Jr.The childhood origins of asthma (COAST) study. Pediatr Allergy Immunol,2002,15:38-43
9. Peric A, Vojvodic D, Radulovic V, et al.Cytokine levels in nasal secretions in asthmatic and nonasthmatic patients with nasal polyposis. Kulak Burun Bogaz Ihtis Derg,2010,20(3):111-7.
10. Hazlewood LC, Wood LG, Hansbro PM,et al. Dietary lycopene supplementation suppresses Th2 responses and lung eosinophilia in a mouse model of allergic asthma. J Nutr Biochem,2010,38(12):365-8.
11. Tomkinson A, Duez C, Cieslewicz G, et al.A murine IL-4 receptor antagonist that inhibits IL-4-and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J Immunol,2001,(9):5792-800.
12. Wenzel S, Wilbraham D, Fuller R, et al.Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients:results of two phase 2a studies. Lancet,2007,(9596):1422-31.
13. Sampson AP. IL-5 priming of eosinophil function in asthma. Clin Exp Allergy, 2001,31(4):513-7.
14. Menzies-Gow A, Robinson DS.Eosinophils, eosinophilic cytokines (interleukin-5), and antieosinophilic therapy in asthma. Curr Opin Pulm Med,2002,8(1):33-8.
15. Palikhe NS, Kim SH, Cho BY,et al. IL-13 Gene Polymorphisms are Associated With Rhinosinusitis and Eosinophilic Inflammation in Aspirin Intolerant Asthma. Allergy Asthma Immunol Res,2010,2(2):134-40.
16. Nakagome K, Dohi M, Okunishi K, et al.IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism. J Immunol,2007,179(1):284-94.
17. Bottner M, Krieglstein K, Unsicker K. The transforming growth factor-betas:structu-re, signaling, and roles in nervous system development and functions. J Neurochem, 2000,75(6):2227-224.
18. Wrana JL,Attisano L,Carcamo J,et al. TGF-beta signals through a heteromeric protein kinase receptor complex. Cell,1992,71; 1003-101.4.
19. Marek B, Kajdaniuk D, Mazurek U,et al. Quantitative assessment of mRNA TGF-betal in liver tissue in connection with serum mean daily level of TGF-1 in chronic hepatitis B patient Pol Arch Med Wewn,2005,114(2):738-45.
20. Lebensztejn DM, Skiba E, Kaczmarski M,et al. The serum concentration of trans-forming growth factor betal, interleukin 12 and interleukin 5 in children with chronic hepatitis B Pol Merkur Lekarski,2003,15(85):86-8.
21. Reiko H, Kiyo shi T,Masahisa F, et al. Stero id therapy and urinary transforming growth factor-β1 in IgA nephropathy. Am J Kidney Dis,2001,38:1191-1198.
22. Alcorn JF, Rinaldi LM, Jaffe EF, et al.Transforming growth factor-betal suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med, 2007,176(10):974-82.
23. Shen ZJ, Esnault S, Rosenthal LA,et al. Pinl regulates TGF-betal production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest,2008,118(2):479-90.
24. Minshall EM, Leung DY, Martin RJ, et al. Eosinophi-associated TGF-betal mRNA expression and airways fibrosis in bronchial asthma.Am J Resp ir CellMol Biol,1997, 17 (3):326-329.
25. Abdulamir AS, Hafidh RR, Abubakar F. Different inflammatory mechanisms in lungs of severe and mild asthma:crosstalk of NF-kappa-B, TGFbetal, Bax, Bcl-2, IL-4 and IgE. Scand J Clin Lab Invest,2009,69(4):487-95.
26. Liu WD, Lu JR. Serum levels of IL-12, TGFbetal and IgE in children with asthma. Zhong guo Dang Dai Er Ke Za Zhi,2008,10(2):146-8.
27. Macey MR, Sturgill JL, Morales JK, et al. IL-4 and TGF-betal counterbalance one another while regulating mast cell homeostasis. J Immunol,2010,184(9):4688-95.
28. Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-betal:potential role in idiopathic pulmonary fibrosis. Am J Pathol,2005,166(5):1321-32.
29. Ro sendah 1A, Checch in D, Fehniger TE, et al. Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation. Am J Resp ir Cell Mo 1B io 1, 2001,25(1):60-68.
30. Sagara H,Okada T, Okumura K, et al. Activation of TGF-β/Smad-signaling is asso-ciated with airway remodelling in asthma. JA llergy Clin Imm unol,2002,110 (2): 249-54.
31. L e AV, Cho JY,M illerM, et al. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. JImmuno 1,2007,178 (11):7310-7316.
32. Holgate S. Epithelial damage and response. Clin Exp Allergy,2000,30(1):137-141.
33. M c-M illan SJ, Xanthou G, L loyd CM. Manipulat ion of Allergen-induced airway remodeling by t reatment with anti-TGF-beta antibody:effect on the Smad signaling pathway. J Immunol,2005,174 (9):5774-5780.
34.童夏生,罗冬娇,方慧英,等.Smad2/3和Smad7蛋白在血中性粒细胞中的表达与哮喘发病关系的实验性研究.中国临床药理学与治疗学,2009,14(4)：405-409.
35. Nakao A. Is TGF-β1 the key to suppression of human asthma? Trends Immunol,2001, 22(3):115-118.
36. Suqita A,Oqawa H, Azuma M, et al. Antiallergic and Anti-InflammatoryEffects of a Novel IkappaB Kinase beta Inhibitor, IMD-0354, in a MouseModel of Allergic Inflammation. Int Arch Allergy Immunol,2008,148(3):186-198.
37. Finotto S, SanctisGT,Lehr HA, et al. Treatment of allergic airway inflammation and hyperresponsiveness by antisenseinduced local blockade ofGATA-3 exp ression. J Exp Med,2001,193 (10):1247-1260.
38. Narala VR, Ranga R, SmithMR, et al. Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma. Resp ir Res,2007,4 (8): 90.
39. Christine T. Inhibition of ExperimentalAllergic AirwaysDisease by Local App lication of a Cell-Penetrating Dominant-Negative STAT-6 Pep tide.The Journal of Immunology,2007,179 (3):2556-2564.
40. Bottoms SE, Howell JE, Reinhardt AK, et al.Tgf-Beta isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One, 2010,5(3):e9674.
41.阮正英,范广民,童夏生,等.地塞米松对哮喘模型大鼠肺组织病理变化和TGF-β1表达的影响.中国药师,2008,11(3)：255-258.
42.刘建博,韩 慧,杨桥榕,等.肺康颗粒对慢阻肺模型大鼠气道重塑及转化生长因子p1的影响.广州中医药大学学报,2009,26(1)：54-57.
43. CHEN Heng-Hua, SUN J ie, CHEN Qing-mei. Effects of Curcum ine on airway remodeling and TGF-β1 mRNA in asthmatic mice. J FourthMilMed Univ,2009, 30(11):989-992.
44. Ohta S, Oda N, Yokoe T,et al. Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma. Clin Exp Allergy,2010,12:115-119.
45. KONG Ling-min, WANG jian-jun, SHEN Cao, et al. Influences of small doses of Rexithromycin on the production of cytokines in small airway disease. Modern Immunology,2005,25(2):162-165.
2. Liang YF,Zhang WX,Li XX, et al.Changes in urotensin-Ⅱ expression in airway remodelling in asthmatic rats. Zhong guo DangDaiErKeZaZhi,2010,12(4):287-9.
3. Hornton DJ, Rousseau K, McGuckin MA. Structure and function of the polymeric mucins in airways mucus. Annu RevPhysiol,2008,70:459-486.
4. Turner J, Jones CE.Regulation of mucin expression in respiratory diseases. Biochem Soc Trans,2009,37(4):877-81.
5. Rubin BK. Mucus and mucins. Otolaryngol Clin North Am,2010,43(1):27-34.
6. Makinde T, Murphy RF, Agrawal DK.The regulatory role of TGF-beta in airway remodeling in asthma. Immunol Cell Biol,2007,85(5):348-56.
7. Atamas SP,White B. Cytokine regulation of pulmonary fibrosis in scleroderma.Cytokine Growth Factor Rev,2003,14(6):537.
8. Chung SW, Miles FL, Sikes RA,et al. Quantitative modeling and analysis of the transforming growth factor beta signaling pathway. Biophys,2009,96(5):1733-50.
9. David C. Clarke, Xuedong Liu. Decoding the quantitative nature of TGF-β3/Smad signaling.Trends Cell Biol,2008,18(9):430-442.
10. Manuyakorn W, Kamchaisatian W, Atamasirikul K,et al. Serum TGF-betal in atopic asthma. Asian Pac J Allergy Immunol,2008,26(4):185-9.
11. Kenyon,N. J,R. W. Ward,et al. TGF-β1 causes airway fibrosis and increased collagen I and IIImRNA in mice. Thorax,2003,58:772.
12. Chen G, Khalil N. TGF-β1 increases proliferation of airway smooth muscle cells by phosphorylation of map kinases. Respir Res,2006,7(1):2.
13. Sarah J,McMillan,Georgina Xanthou,et al. Manipulation of Allergen-Induced Airway Remodeling by Treatment with Anti-TGF-beta Antibody Effect on the Smad Signaling Pathway.The Journal of Immunology,2005,174:5774-5780.
14. Oku H, Shimizu T, Kawabata T,et al.Antifibrotic action of pirfenidone and prednisolone:different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol, 2008,590(1-3):400-8.
15. RamachandraRao SP, Zhu Y, Ravasi T,et al. Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol,2009,20(8):1765-75.
16. Di Sario A, Bendia E, Svegliati Baroni G,et al. Effect of pirfenidone on rat hepatic stellate cell proliferation and collagen production. J Hepatol,2002,37(5):584-591.
17. Tobin MJ. Asthma, airway biology, and nasal disorders in AJRCCM2001. Am J Respir Crit Care Med,2002,165:598-618.
18. Trautmann A,Schmid-Grendelmeier P, Kruger K, etal. T cells and eosinophils cooperate in the induction of bronchial epithelial cell apoptosis in asthma. J Allergy Clin Immuunol,2002,109:329-337.
19. WEN Xiu-fang, ZHOU Xiang-dong. Goblet cellsmetaplasia and secreting regulation of air way epithelium. International Journal of Pathology and Clinical Medicine,2008, 28(1):0059-05.
20.王莹,王华英,谢强敏,等.哮喘小鼠气道上皮杯状细胞增生模型.中国药理学通报,2006,22(22)：251-253.
21. Martinez-Anton A,Debolos C,Garrido M,et al. Mucin genes have different expression patterns in healthy and diseased upper airway mucosa. Clin Exp Allergy,2006,36(4): 448-457.
22. Sutherland ER, Martin RJ. Airway inflammation in chronic obstructive pulmonary isease:comparisons with asthma. JAllergy Clin Immunol,2003,112:819-827
23. Tillie-Leblond I,Gosset P, Tonnel AB.Inflammatory events in severe acute asthma.Allergy,2005,60:23-29.
24. Pabst R. Animal model for asthma:controversial aspects and unsolved problems.Pathobiology,2003,70(5):260-265.
25. Hayashi T,Adachi Y,Hasegawa K,et al.Less sensitivity for late airway inflammation in males than females in BALB/c mice.Scand J Immunol,2003,57(6):562.
26. Fuchs B, Braun A. Improved mouse models of allergy and allergic asthma-chances beyond ovalbumin. Curr Drug Targets,2008,9(6):495-502.
1. Tomasiak-Lozowska MM, Bodzenta-Lukaszyk A, Tomasiak M.et al. The role of interleukin 13 and interleukin 5 in asthma. Postepy Hig Med Dosw (Online), 2010,64:146-55.
2. Antoniu SA.Cytokine antagonists for the treatment of asthma:progress to date. BioDrugs,2009,23(4):241-51.
3. LI Ming-cai, HE Shao-heng. Role of transforming growth factor-β in the airway inflammation and remodeling in asthma. Chinese Journal of Pathophysiology,2004, 20(8):1527-1530.
4. Moore B, Murphy RF, Agrawal DK. Interaction of tgf-beta with immune cells in airway disease. Curr Mol Med,2008,8(5):427-36.
5. Mc-Millan SJ, Xanthou G, L loyd CM. Manipulat ion of Allergen-induced airway remodeling by treatment with anti-TGF-beta ant ibody:effect on the Smad signaling pathway. J Immunol,2005,174 (9):5774-5780.
6. L e AV, Cho JY,M illerM, et al. Inh ibit ion of allergen induced airw ay remodeling in Smad-3deficient mice. J Immuno 1,2007,178 (11):7310-7316.
7. Ro sendah 1 A, Checch in D, Fehniger TE, et al.Activation of the TGF-beta/act ivin-Smad-pathway during allergic airway inflammation. Am J Resp ir CellMo 1B io 1,2001,25(1):60-68.
8. Bataller R, Brenner D A. Liver fibrosis. J Clin Invest,2005,115(2):209-218.
9. Collard HR. Idiopathic pulmonary fibrosis and pirfenidone. Eur Respir,2010, 35(4):728-9.
10. Mitani Y, Sato K, Muramoto Y, Karakawa T,et al. Superoxide scavenging activity of pirfenidone-iron complex. Biochem Biophys Res Commun,2008,372(1):19-23.
11. Mei S, Yao W, Zhu Y, et al. Protection of pirfenidone against an early phase of oleic acid-induced acute lung injury in rats. J Pharmacol Exp Ther,2005,313(1):379-388.
12. Murakami M, Kawachi H, Ogawa K, et al.Receptor expression modulates the specificity of transforming growth factor-beta signaling pathways. Genes Cells, 2009,14(4):469-82.
13. Wrana JL, Attisano L, Carcamo J, Zentella A, Doody J, et al. TGF-beta signals through a heteromeric protein kinase receptor complex. Cell,1992,71:1003-1014.
14. Sekelsky J J,Newfeld S,Raftery L A,et al.Genetic characterization and cloning of Mothers against dpp,a gene required fordecapentaplegic function in Drosophila melanogaster. Genetics,1995,139:1347-1358.
15. Lin X, Chen Y, Meng A, Feng X.Termination of TGF-beta superfamily signaling through SMAD dephosphorylation--a functional genomic view. J Genet Genomics, 2007,34(1):1-9.
16. Bornstein S, White R, Malkoski S,et al. Smad4 loss in mice causes spontaneous head and neck cancer with increased genomic instability and inflammation. Clin Invest, 2009,119(11):3408-19.
17. Brown KA, Pietenpol JA, Moses HL.A tale of two proteins:differential roles and regulation of Smad2 and Smad3 in TGF-beta signaling. J Cell Biochem,2007, 101(1):9-33.
18. Derynck R, Zhang YE. Smad-dependent and Smad-independent pathways in TGF-beta family signaling. nature,2003,425(6958):577.
19. WANG Li, HUO Yan-ying, ZHANG Kai-tai, et al. The Effect of Smad7 Gene on Nuclear Translocation of Smad2/3/4. LETTERS IN BIOTECHNOLOGY,2005, 16(2):128-130.
20. Lin HM, Lee JH, Yadav H.Transforming growth factor-beta/Smad3 signaling regulates insulin gene transcription and pancreatic islet beta-cell function. J Biol Chem,2009,284(18):12246-57.
21. CHENG Hong, SONG Enfeng. Effects of Eucommia on TGF-β1/ Smad Signaling Pathway in Renal Interstitial Fibrosis in Rats with Unilateral Ureteral Obstruction. CJ ITWN,2009,10(6):502-504.
22. Zhou L, Fu P, Huang XR, et al. Mechanism of chronic aristolochic acid nephropathy: role of Smad3. Am J Physiol Renal Physiol,2010,298(4):F1006-17.
23. Schiffer M, von Gersdorff G, Bitzer M, et al. Smad proteins and transforming growth factor-beta signaling. Kidney Int Suppl,2000,77:S45-S52.
24. Wang LF, Zhang L, Zhang RY,et al. Relationship between expression of Smad and ventricular remodeling after myocardial infarction in rats. Zhonghua Xin Xue Guan Bing Za Zhi,2005,33(10):932-5.
25. Makinde T,M urphy RF,A grawal DK,et al. The regulatory role of TGF-beta in airway remodeling in asthma. Immuno 1 Cell Biol,2007,85(5):348-356.
26. Magnan A,Retornaz F,Tsicopoulos A,et al. Altered compartmentalization of transforming growth factor-beta in asthmatic airways. Clin Exp Allergy,1997,27: 389-395.
27. CHEN HengHua,SUN Jie,CHEN Qing-mei. Effects of Curcine on airway remodeling and TGF-β1 mRNA in asthmatic mice. J Fourth MilMed Univ,2009,30(11):989-992.
28. REDINGTON AE, MADDEN J, FREW AJ, et al. Transforming Growth Factor-β1 in Asthma Measurement in Broncho alveolar Lavage Fluid. Am J Respir Crit Care Med, 1997,156:642-647.
29. Shen ZJ, Esnault S, Rosenthal LA,et al. Pinl regulates TGF-betal production by-activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest,2008,118(2):479-90.
30. Liu JB, Zhang ZX, Xu YJ,et al.Effects of glucocorticoid on airway mucus secretion in asthma:experiment with asthmatic mouse model. Zhonghua Yi Xue Za Zhi,2006, 86(35):2491-4.
31. Komatsu K, Jono H, Lim JH,et al. Glucocorticoids inhibit nontypeable Haemophilus influenzae-induced MUC5AC mucin expression via MAPK phosphatase-1-dependent inhibition of p38 MAPK. Biochem Biophys Res Commun,2008,377(3):763-8.
32. LIU Ping-li, LV Li-li. Effects of Dexamethsone on proliferation of airway smooth muscle cells and transforming growth factor-β1 in chronic asthma mice. China Journal of Modern Medicine,2008,18(10):1353-1356.
1. Moore B, Murphy RF, Agrawal DK. Interaction of tgf-beta with immune cells in airway disease. Curr Mol Med,2008,8(5):427-36.
2. Hyvarinen MK, Kotaniemi-Syrjanen A, Reijonen TM, et al.Eosinophil activity in infants hospitalized for wheezing and risk of persistent childhood asthma. Pediatr Allergy Immunol,2010,21(11):96-103.
3. Wang HB, Ghiran I, Matthaei K, Weller PF. Airway eosinophils:allergic inflamm-ation recruited professional antigen-presenting cells. J Immunol,2007,179 (11): 7585-92.
4. Walsh ER, Stokes K, August A. The role of eosinophils in allergic airway inflammation. Discov Med,2010,9(47):357-62.
5. Yuksel B, Aydemir C, Ustundag G,et al. The effect of treatment with montelukast on levels of serum interleukin-10, eosinophil cationic protein, blood eosinophil counts, and clinical parameters in children with asthma. Turk J Pediatr,2009,51 (5):460-5.
6. Message SD, Laza-Stanca V, Mallia P,et al. Rhinovirus-induced lower respiratory illness is increased in asthma and related to virus load and Th1/2 cytokine and IL-10 production. Proc Natl Acad Sci USA,2008,105(36):13562-7.
7. Shin SM, Kim YH, Choi BK,et al.4-1BB triggers IL-13 production from T cells to limit the polarized, Thl-mediated inflammation. J Leukoc Biol,2007,81(6):1455-65.
8. Lemanske RF Jr.The childhood origins of asthma (COAST) study. Pediatr Allergy Immunol,2002,15:38-43
9. Peric A, Vojvodic D, Radulovic V, et al.Cytokine levels in nasal secretions in asthmatic and nonasthmatic patients with nasal polyposis. Kulak Burun Bogaz Ihtis Derg,2010,20(3):111-7.
10. Hazlewood LC, Wood LG, Hansbro PM,et al. Dietary lycopene supplementation suppresses Th2 responses and lung eosinophilia in a mouse model of allergic asthma. J Nutr Biochem,2010,38(12):365-8.
11. Tomkinson A, Duez C, Cieslewicz G, et al.A murine IL-4 receptor antagonist that inhibits IL-4-and IL-13-induced responses prevents antigen-induced airway eosinophilia and airway hyperresponsiveness. J Immunol,2001,(9):5792-800.
12. Wenzel S, Wilbraham D, Fuller R, et al.Effect of an interleukin-4 variant on late phase asthmatic response to allergen challenge in asthmatic patients:results of two phase 2a studies. Lancet,2007,(9596):1422-31.
13. Sampson AP. IL-5 priming of eosinophil function in asthma. Clin Exp Allergy, 2001,31(4):513-7.
14. Menzies-Gow A, Robinson DS.Eosinophils, eosinophilic cytokines (interleukin-5), and antieosinophilic therapy in asthma. Curr Opin Pulm Med,2002,8(1):33-8.
15. Palikhe NS, Kim SH, Cho BY,et al. IL-13 Gene Polymorphisms are Associated With Rhinosinusitis and Eosinophilic Inflammation in Aspirin Intolerant Asthma. Allergy Asthma Immunol Res,2010,2(2):134-40.
16. Nakagome K, Dohi M, Okunishi K, et al.IL-5-induced hypereosinophilia suppresses the antigen-induced immune response via a TGF-beta-dependent mechanism. J Immunol,2007,179(1):284-94.
17. Bottner M, Krieglstein K, Unsicker K. The transforming growth factor-betas:structu-re, signaling, and roles in nervous system development and functions. J Neurochem, 2000,75(6):2227-224.
18. Wrana JL,Attisano L,Carcamo J,et al. TGF-beta signals through a heteromeric protein kinase receptor complex. Cell,1992,71; 1003-101.4.
19. Marek B, Kajdaniuk D, Mazurek U,et al. Quantitative assessment of mRNA TGF-betal in liver tissue in connection with serum mean daily level of TGF-1 in chronic hepatitis B patient Pol Arch Med Wewn,2005,114(2):738-45.
20. Lebensztejn DM, Skiba E, Kaczmarski M,et al. The serum concentration of trans-forming growth factor betal, interleukin 12 and interleukin 5 in children with chronic hepatitis B Pol Merkur Lekarski,2003,15(85):86-8.
21. Reiko H, Kiyo shi T,Masahisa F, et al. Stero id therapy and urinary transforming growth factor-β1 in IgA nephropathy. Am J Kidney Dis,2001,38:1191-1198.
22. Alcorn JF, Rinaldi LM, Jaffe EF, et al.Transforming growth factor-betal suppresses airway hyperresponsiveness in allergic airway disease. Am J Respir Crit Care Med, 2007,176(10):974-82.
23. Shen ZJ, Esnault S, Rosenthal LA,et al. Pinl regulates TGF-betal production by activated human and murine eosinophils and contributes to allergic lung fibrosis. J Clin Invest,2008,118(2):479-90.
24. Minshall EM, Leung DY, Martin RJ, et al. Eosinophi-associated TGF-betal mRNA expression and airways fibrosis in bronchial asthma.Am J Resp ir CellMol Biol,1997, 17 (3):326-329.
25. Abdulamir AS, Hafidh RR, Abubakar F. Different inflammatory mechanisms in lungs of severe and mild asthma:crosstalk of NF-kappa-B, TGFbetal, Bax, Bcl-2, IL-4 and IgE. Scand J Clin Lab Invest,2009,69(4):487-95.
26. Liu WD, Lu JR. Serum levels of IL-12, TGFbetal and IgE in children with asthma. Zhong guo Dang Dai Er Ke Za Zhi,2008,10(2):146-8.
27. Macey MR, Sturgill JL, Morales JK, et al. IL-4 and TGF-betal counterbalance one another while regulating mast cell homeostasis. J Immunol,2010,184(9):4688-95.
28. Willis BC, Liebler JM, Luby-Phelps K, et al. Induction of epithelial-mesenchymal transition in alveolar epithelial cells by transforming growth factor-betal:potential role in idiopathic pulmonary fibrosis. Am J Pathol,2005,166(5):1321-32.
29. Ro sendah 1A, Checch in D, Fehniger TE, et al. Activation of the TGF-beta/activin-Smad2 pathway during allergic airway inflammation. Am J Resp ir Cell Mo 1B io 1, 2001,25(1):60-68.
30. Sagara H,Okada T, Okumura K, et al. Activation of TGF-β/Smad-signaling is asso-ciated with airway remodelling in asthma. JA llergy Clin Imm unol,2002,110 (2): 249-54.
31. L e AV, Cho JY,M illerM, et al. Inhibition of allergen-induced airway remodeling in Smad 3-deficient mice. JImmuno 1,2007,178 (11):7310-7316.
32. Holgate S. Epithelial damage and response. Clin Exp Allergy,2000,30(1):137-141.
33. M c-M illan SJ, Xanthou G, L loyd CM. Manipulat ion of Allergen-induced airway remodeling by t reatment with anti-TGF-beta antibody:effect on the Smad signaling pathway. J Immunol,2005,174 (9):5774-5780.
34.童夏生,罗冬娇,方慧英,等.Smad2/3和Smad7蛋白在血中性粒细胞中的表达与哮喘发病关系的实验性研究.中国临床药理学与治疗学,2009,14(4)：405-409.
35. Nakao A. Is TGF-β1 the key to suppression of human asthma? Trends Immunol,2001, 22(3):115-118.
36. Suqita A,Oqawa H, Azuma M, et al. Antiallergic and Anti-InflammatoryEffects of a Novel IkappaB Kinase beta Inhibitor, IMD-0354, in a MouseModel of Allergic Inflammation. Int Arch Allergy Immunol,2008,148(3):186-198.
37. Finotto S, SanctisGT,Lehr HA, et al. Treatment of allergic airway inflammation and hyperresponsiveness by antisenseinduced local blockade ofGATA-3 exp ression. J Exp Med,2001,193 (10):1247-1260.
38. Narala VR, Ranga R, SmithMR, et al. Pioglitazone is as effective as dexamethasone in a cockroach allergen-induced murine model of asthma. Resp ir Res,2007,4 (8): 90.
39. Christine T. Inhibition of ExperimentalAllergic AirwaysDisease by Local App lication of a Cell-Penetrating Dominant-Negative STAT-6 Pep tide.The Journal of Immunology,2007,179 (3):2556-2564.
40. Bottoms SE, Howell JE, Reinhardt AK, et al.Tgf-Beta isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. PLoS One, 2010,5(3):e9674.
41.阮正英,范广民,童夏生,等.地塞米松对哮喘模型大鼠肺组织病理变化和TGF-β1表达的影响.中国药师,2008,11(3)：255-258.
42.刘建博,韩 慧,杨桥榕,等.肺康颗粒对慢阻肺模型大鼠气道重塑及转化生长因子p1的影响.广州中医药大学学报,2009,26(1)：54-57.
43. CHEN Heng-Hua, SUN J ie, CHEN Qing-mei. Effects of Curcum ine on airway remodeling and TGF-β1 mRNA in asthmatic mice. J FourthMilMed Univ,2009, 30(11):989-992.
44. Ohta S, Oda N, Yokoe T,et al. Effect of tiotropium bromide on airway inflammation and remodelling in a mouse model of asthma. Clin Exp Allergy,2010,12:115-119.
45. KONG Ling-min, WANG jian-jun, SHEN Cao, et al. Influences of small doses of Rexithromycin on the production of cytokines in small airway disease. Modern Immunology,2005,25(2):162-165.