哮喘豚鼠气道TGF-β_1、IL-13、VEGF表达关系及黄芪干预的研究
摘要
目的:探讨哮喘豚鼠气道中TGF-β1、IL-13、VEGF表达的变化,及黄芪对其的干预作用。
方法:健康雄性豚鼠40只随机分成4组:正常对照组(A组) ,模型组(B组),黄芪注射液组( C组) ,地塞米松组(D组),每组10只。以腹腔内注射联合雾化吸入卵蛋白复制哮喘气道重塑模型,末次激发后24h处死豚鼠,以图像分析仪分析气道重塑情况,以免疫组化方法测气道中TGF-β1、IL-13、VEGF的表达。
结果:
1.哮喘气道平滑肌增生是气道重塑的主要原因,黄芪注射液可通过抑制气道平滑肌增生,从而达到抑制气道重塑的目的。
2.免疫组化(IH )显示气道中TGF-β1、IL-13、VEGF的表达在B组中表达较A组高,C组与D组较B组均明显降低,差异有显著性( P < 0.01)。
结论:
1.在哮喘豚鼠气道重塑模型气道上皮中TGF-β1、IL-13、VEGF的表达明显增高,支持其在哮喘发病中的作用。
2.黄芪治疗哮喘的机制可能与抑制TGF-β1、IL-13、VEGF的表达生成有关。
Objective To investigate the change of TGF-β1、IL-13、VEGF in the the airway of asthmatic guinea pigs.more importantly,to study the effects of Huang Qi on TGF-β1、Interleukin-13、VEGF in the the airway of asthmatic guinea pigs and explore the possible therapeutic mechanism of Huang Qi on asthma .
Methods Forty adult male guinea pigs were randomly divided into control group (group A),asthmatic group (group B), arsenic huang qi group (group C) and dexamethasone group(group D),ten in each group. Asthmatic airway remodeling model was established by ovalbumin intraperitoneal combined with inhalation . The guinea pigs were killed at 24 h after the last challenge . Use the image analysis device to analysis the information of the airway remodeling. Immunohistochemistry detected the expression of TGF-β1、Interleukin-13、VEGF in the lung tissue.
Results The main cause of airway remodeling is hyperplasia of airway smooth muscle,Huangqi can suppress the airway remodeling by restrain the hyperplasia of airway smooth muscle. The expression of TGF-β1、IL-13、VEGF in lung of group B were significantly higher than that in groupA;compared with group B,there were significant decrease in group C and group D. the differences were significant (P < 0.01) .
Conclusions
1. Expression of TGF-β1、IL-13、VEGF in the airway of guinea pig with asthma were remarkably increased.
2. Huang qi may achieve its anti-inflammatory mechanism based on reducing the production of TGF-β1、IL-13、VEGF in the airway.
方法:健康雄性豚鼠40只随机分成4组:正常对照组(A组) ,模型组(B组),黄芪注射液组( C组) ,地塞米松组(D组),每组10只。以腹腔内注射联合雾化吸入卵蛋白复制哮喘气道重塑模型,末次激发后24h处死豚鼠,以图像分析仪分析气道重塑情况,以免疫组化方法测气道中TGF-β1、IL-13、VEGF的表达。
结果:
1.哮喘气道平滑肌增生是气道重塑的主要原因,黄芪注射液可通过抑制气道平滑肌增生,从而达到抑制气道重塑的目的。
2.免疫组化(IH )显示气道中TGF-β1、IL-13、VEGF的表达在B组中表达较A组高,C组与D组较B组均明显降低,差异有显著性( P < 0.01)。
结论:
1.在哮喘豚鼠气道重塑模型气道上皮中TGF-β1、IL-13、VEGF的表达明显增高,支持其在哮喘发病中的作用。
2.黄芪治疗哮喘的机制可能与抑制TGF-β1、IL-13、VEGF的表达生成有关。
Objective To investigate the change of TGF-β1、IL-13、VEGF in the the airway of asthmatic guinea pigs.more importantly,to study the effects of Huang Qi on TGF-β1、Interleukin-13、VEGF in the the airway of asthmatic guinea pigs and explore the possible therapeutic mechanism of Huang Qi on asthma .
Methods Forty adult male guinea pigs were randomly divided into control group (group A),asthmatic group (group B), arsenic huang qi group (group C) and dexamethasone group(group D),ten in each group. Asthmatic airway remodeling model was established by ovalbumin intraperitoneal combined with inhalation . The guinea pigs were killed at 24 h after the last challenge . Use the image analysis device to analysis the information of the airway remodeling. Immunohistochemistry detected the expression of TGF-β1、Interleukin-13、VEGF in the lung tissue.
Results The main cause of airway remodeling is hyperplasia of airway smooth muscle,Huangqi can suppress the airway remodeling by restrain the hyperplasia of airway smooth muscle. The expression of TGF-β1、IL-13、VEGF in lung of group B were significantly higher than that in groupA;compared with group B,there were significant decrease in group C and group D. the differences were significant (P < 0.01) .
Conclusions
1. Expression of TGF-β1、IL-13、VEGF in the airway of guinea pig with asthma were remarkably increased.
2. Huang qi may achieve its anti-inflammatory mechanism based on reducing the production of TGF-β1、IL-13、VEGF in the airway.
引文
1.钟南山,支气管哮喘-基础与临床,人民卫生出版社,2006,438.
2.刘鑫,戴爱国.柴朴汤对哮喘豚鼠嗜酸粒细胞凋亡及气道重塑的影响四川中医,2005,23(6):11-12.
3.鲍志坚,徐俭朴,楼景英.黄芪复方对哮喘患者气道高反应性的影响[ J ].浙江中西医结合杂志, 2002, 11 (2) :30 - 31.
4.苏南湘,张四方,何明大.黄芪注射液为主治疗慢性支气管炎40例[ J ].湖南中医杂志, 2003, 19 (6) : 30 - 31.
5.张洁,孙秀珍,田蓉。黄芪对哮喘患者气道反应性的影响第四军医大学学报2006; 27 (8) :701-702.
6.Wen FQ,Kohyama T, Skold CM,et al.Glucocorticoids molecular TGF-beta production by human fetal lung fibroblast[J]. Inflammation,2003,27(1):9-19.
7.李明才,何韶衡,转化生长因子-β与哮喘,《生命的化学》2003,23 (1) :57-58.
8.林晓明,何建猷,梁标,白介素-13在哮喘发病机制中的作用,国际病理科学与临床杂志,2005,25(6):539-542.
9. Saez AO, Du T, Wang NS, et al·Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig·J ApplPhysiol,1996,80:437-444.
10. JamesAL, ParéPD , Hogg JC.The mechanics of airway narrowing in asthma.Am Rev Respir Dis,1989,139:242-246.
11. Bramley AM, Thomson RJ, Roberts CR, et al·Excessive bronchoconstriction in asthma is due to decreased airway elastance·Eur Respir J,1994,7:337-341.
12. James AL, Hogg JC, Dunn LA, et al·The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening·Am Rev Respir Dis,1988,138:136-139.
13. Isaka Y, Tsujie M, Ando Y ,et al. Transforming growth factor-beta 1 antisense oligodeoxy-nucleotides block interstitial fibrosis in unilateral ureteral obstruction[J]. Kidney Int ,2000 ,58(5) :1885-1892.
14. Khalil N,O’Cnnor RN,Flanders KC,et a1.TGF-β,but not TGF-βor TGF-βis diferentially present on epithelial cellsof advanced pulmonary fibrosis: all immunohisto chemicl study.Am J Respire cell Mol Biol,1996,14(2):131.
15. Shima Y,Nakao K,Nakashima T,el a1.Activation of caspase-8 intransforming growth factor-beta-induced apoptosis of human hepatoma cells[J].Hepatology,1999,30:1215.
16. Duvernelle C ,Freund V ,Frossard N ,et al . Transforming growth factor2 beta and its role in ast hma. Pulm Pharmacol Ther ,2003 , 16 (4) :181-196.
17.张敏,吴壮,徐军。损伤气道上皮组织转化在气道重塑中的作用[J]医学研究生学报2004,11(17):966-969.
18.LI L, XIA Y, NGU YEN A, et al. Effects of Th2 cytokines on chemokine expression in the lung : IL-13 potently induces eotaxin expression by airway epithelial cells [ J ] . J Immunol ,1999 ,162.
19. Yang G, Volk A , Petley T et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness,inflammation and airway remodeling.Cytokine,2004 ,28 (6) :224.
20. Camoretti - Mercado B , Solway J . Transforming growth factor -β1 and disorders of the lung[J ] . Cell Biochem Biophys ,2005 ,43 :131 -148.
21. Kumar PK,Herbert C,Yaog M ,et a1.Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma[J].Clin Exp Allergy,2002,32:1104-1111.
22. Saito A,Okazaki,H,Sugawara I.et al. Potential action of IL-4 and IL-13 As fibrogenic factors on lung fibrolasts in vitro[J].Allergy,Immunol, 2003,132:168-176.
23. Machino T,Hashimoto S,Con Y,et a1.Interleukin-4 and interleukin-13-induce fibronectin production by human lung fibroblasts [J].Aller Inter,2001,50:197-202.
24. Wen FQ,Kohyama T,Liu XD,et a1.Interleukin-4 and inter-leukin-13 enhanced growth factor-production in cultured human bronchial epithelial cells is attenuated by interferon-β.Am J RespirCHt CareMed,2002,26:484-490.
25.Laporte JC,Moode PE,Baraldo S,et a1.Direct effects of inter-leukin-13 on signaliI pathways for physiological responses in cultured human airway smooth muscle cells[J].Am J Respir Crit CareMed,2001,164:141-148.
26.徐振晔,王中奇,朱晏伟.等.肺岩宁对晚期非小细胞肺癌生长转移和血清VEGF的影响[J].上海中医药大学学报,2003,17(1):18-22.
27.张苗,蒋春明,孙净。黄芪对腹膜透析相关腹膜间皮细胞VEGF分泌和表达的影响医学临床研究2005, 22(l2):112-114.
28 Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.Diabetes. 1999 Oct;48(10):899-906.
29.Hashimoto M, Tanaka H, Abe S. Quantitative analysis of bronchial wall vascularity in the medium and small airways of patients with asthma and COPD.Chest,2005,127(3):965-972.
30.Asai K, Kanazawa H, Kamoi H, et al. Increased levels of vascular endothelial growth factor induced sputum in asthmatic patients.Clin Exp Allergy,2003,33(5):595 -599.
31.Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent.Am J Physiol Lung Cell Mol Physiol,2004,286(3): L539-545.
32.Hirst SJ, Twort CH, Lee TH. Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol, 2000,23(3):335-344.
1.钟南山.支气管哮喘一基础与临床,人民卫生出版社,2006,438.
2.刘鑫,戴爱国.黄芪对哮喘豚鼠嗜酸粒细胞凋亡及气道重塑的影响四川中医,2005,23(6):11—12.
3.鲍志坚,徐俭朴,楼景英.黄芪复方对哮喘患者气道高反应性的影响[J].浙江中西医结合杂志,2002,11(2):30—31.
4.苏南湘,张四方,何明大.黄芪注射液为主治疗慢性支气管炎40例[J].湖南医杂志,2003,19(6):30—31.
5.张洁,孙秀珍,田蓉。黄芪对哮喘患者气道反应性的影响第四军医大学学报2006:27(8):701-702.
6.Wen FQ,Kohyama T, Skold CM,et al.Glucocorticoids molecular TGF-beta production by human fetal lung fibroblast[J]. Inflammation,2003, 27(1):9-19.
7.李明才,何韶衡,转化生长因子-β与哮喘,《生命的化学》2003,23(1):57—58.
8.林晓明何建猷梁标,白介素13在哮喘发病机制中的作用,国际病理科学与临床杂志,2005,25(6)539—542.
9. Saez AO, Du T, Wang NS, et al·Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig·J ApplPhysiol,1996,80:437-444·
10. JamesAL, ParePD , Hogg JC.The mechanics of airway narrowing in asthma.Am Rev Respir Dis,1989,139:242-246
11. Bramley AM, Thomson RJ, Roberts CR, et al·Excessive bronchoconstriction in asthma is due to decreased airway elastance·Eur Respir J,1994,7:337-341.
12. James AL, Hogg JC, Dunn LA, et al·The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening·Am Rev Respir Dis,1988,138:136-13.
13. Isaka Y, Tsujie M, Ando Y ,et al. Transforming growth factor-beta 1 antisense oligodeoxy-nucleotides block interstitial fibrosis in unilateral ureteral obstruction[J]. Kidney Int ,2000 ,58(5) :1885-1892.
14. KhalilN, O'CnnorRN, Flanders KC, et al. TGF-β, but not TGF-βor TGF-3 is diferentially present on epithelial cellsof advanced pulmonary fibrosis: all immunohisto chemicl study. Am J Respire cell Mol Biol, 1996,14(2):131.
15. Shima Y, Nakao K, Nakashima T, el al. Activation of caspase-8 intransforming growth factor-beta-induced apoptosis of human hepatoma cells[J]. Hepatology,1999, 30:1215.
16. Duvernelle C ,Freund V ,Frossard N ,et al. Transforming growth factor2 beta and its role in ast hma. Pulm Pharmacol Ther ,2003 , 16 (4) :181-196.
17.张敏,吴壮,徐军。损伤气道上皮组织转化在气道重塑中的作用[J]医学研究生学报2004.,11(17)966—969.
18.LI L, XIA Y, NGU YEN A, et al. Effects of Th2 cytokines on chemokine expression in the lung : IL-13 potently induces eotaxin expression by airway epithelial cells [ J ] . J Immunol ,1999 ,162.
19. Yang G, Volk A , Petley T et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness,inflammation and airway remodeling.Cytokine,2004 ,28 (6) :224.
20. Camoretti - Mercado B , Solway J . Transforming growth factor -β1 and disorders of the lung[J ] . Cell Biochem Biophys ,2005 ,43 :131 -148.
21. Kumar PK, Herbert C, Yaog M , et al. Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma[J]. Clin Exp Allergy, 2002, 32:1104—1111.
22. Saito A, Okazaki, H, Sugawara I. et al. Potential action of IL-4 and IL-13 As fibrogenic factors on lung fibrolasts in vitro[J]. Allergy, Immunol, 2003,132:168-176
23. Machino T, Hashimoto S, Con Y, et al. Interleukin-4 and interleukin-13-induce fibronectin production by human lung fibroblasts [J]. Aller Inter, 2001, 50: 197-202.
24.Wen FQ, KohyamaT, Liu XD, etal. Interleukin-4 and inter-leukin-13 enhanced growth factor-production in cultured human bronchial epithelial cells is attenuated by interferon-β.Am J RespirCHt CareMed,2002, 26:484—490.
25. Laporte JC,Moode PE,Baraldo S,et al. Direct effects of inter-leukin-13 on signaliI pathways for physiological responses in cultured human airway smooth muscle cells[J]. Am J Respir Crit CareMed,2001,164:141-148.
26 Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.Diabetes. 1999 Oct;48(10):899-906.
27.Hashimoto M, Tanaka H, Abe S. Quantitative analysis of bronchial wall vascularityin the medium and small airways of patients with asthma and COPD.Chest,2005,127(3):965-972.
28.Asai K, Kanazawa H, Kamoi H, et al. Increased levels of vascular endothelial growth factor induced sputum in asthmatic patients.Clin Exp Allergy,2003,33(5):595 -599.
29.Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent.Am J Physiol Lung Cell Mol Physiol,2004,286(3): L539-545.
30.Hirst SJ, Twort CH, Lee TH. Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol, 2000,23(3):335-344.
31.徐振晔,王中奇,朱晏伟.等.肺岩宁对晚期非小细胞肺癌生长转移和血清VEGF的影响[J].上海中医药大学学报,2003,17(1):18—22.
32.张苗蒋春明孙净。黄芪对腹膜透析相关腹膜问皮细胞VEGF。分泌和表达的影响医学临床研究2005,22(12):112—114.
2.刘鑫,戴爱国.柴朴汤对哮喘豚鼠嗜酸粒细胞凋亡及气道重塑的影响四川中医,2005,23(6):11-12.
3.鲍志坚,徐俭朴,楼景英.黄芪复方对哮喘患者气道高反应性的影响[ J ].浙江中西医结合杂志, 2002, 11 (2) :30 - 31.
4.苏南湘,张四方,何明大.黄芪注射液为主治疗慢性支气管炎40例[ J ].湖南中医杂志, 2003, 19 (6) : 30 - 31.
5.张洁,孙秀珍,田蓉。黄芪对哮喘患者气道反应性的影响第四军医大学学报2006; 27 (8) :701-702.
6.Wen FQ,Kohyama T, Skold CM,et al.Glucocorticoids molecular TGF-beta production by human fetal lung fibroblast[J]. Inflammation,2003,27(1):9-19.
7.李明才,何韶衡,转化生长因子-β与哮喘,《生命的化学》2003,23 (1) :57-58.
8.林晓明,何建猷,梁标,白介素-13在哮喘发病机制中的作用,国际病理科学与临床杂志,2005,25(6):539-542.
9. Saez AO, Du T, Wang NS, et al·Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig·J ApplPhysiol,1996,80:437-444.
10. JamesAL, ParéPD , Hogg JC.The mechanics of airway narrowing in asthma.Am Rev Respir Dis,1989,139:242-246.
11. Bramley AM, Thomson RJ, Roberts CR, et al·Excessive bronchoconstriction in asthma is due to decreased airway elastance·Eur Respir J,1994,7:337-341.
12. James AL, Hogg JC, Dunn LA, et al·The use of the internal perimeter to compare airway size and to calculate smooth muscle shortening·Am Rev Respir Dis,1988,138:136-139.
13. Isaka Y, Tsujie M, Ando Y ,et al. Transforming growth factor-beta 1 antisense oligodeoxy-nucleotides block interstitial fibrosis in unilateral ureteral obstruction[J]. Kidney Int ,2000 ,58(5) :1885-1892.
14. Khalil N,O’Cnnor RN,Flanders KC,et a1.TGF-β,but not TGF-βor TGF-βis diferentially present on epithelial cellsof advanced pulmonary fibrosis: all immunohisto chemicl study.Am J Respire cell Mol Biol,1996,14(2):131.
15. Shima Y,Nakao K,Nakashima T,el a1.Activation of caspase-8 intransforming growth factor-beta-induced apoptosis of human hepatoma cells[J].Hepatology,1999,30:1215.
16. Duvernelle C ,Freund V ,Frossard N ,et al . Transforming growth factor2 beta and its role in ast hma. Pulm Pharmacol Ther ,2003 , 16 (4) :181-196.
17.张敏,吴壮,徐军。损伤气道上皮组织转化在气道重塑中的作用[J]医学研究生学报2004,11(17):966-969.
18.LI L, XIA Y, NGU YEN A, et al. Effects of Th2 cytokines on chemokine expression in the lung : IL-13 potently induces eotaxin expression by airway epithelial cells [ J ] . J Immunol ,1999 ,162.
19. Yang G, Volk A , Petley T et al. Anti-IL-13 monoclonal antibody inhibits airway hyperresponsiveness,inflammation and airway remodeling.Cytokine,2004 ,28 (6) :224.
20. Camoretti - Mercado B , Solway J . Transforming growth factor -β1 and disorders of the lung[J ] . Cell Biochem Biophys ,2005 ,43 :131 -148.
21. Kumar PK,Herbert C,Yaog M ,et a1.Role of interleukin-13 in eosinophil accumulation and airway remodelling in a mouse model of chronic asthma[J].Clin Exp Allergy,2002,32:1104-1111.
22. Saito A,Okazaki,H,Sugawara I.et al. Potential action of IL-4 and IL-13 As fibrogenic factors on lung fibrolasts in vitro[J].Allergy,Immunol, 2003,132:168-176.
23. Machino T,Hashimoto S,Con Y,et a1.Interleukin-4 and interleukin-13-induce fibronectin production by human lung fibroblasts [J].Aller Inter,2001,50:197-202.
24. Wen FQ,Kohyama T,Liu XD,et a1.Interleukin-4 and inter-leukin-13 enhanced growth factor-production in cultured human bronchial epithelial cells is attenuated by interferon-β.Am J RespirCHt CareMed,2002,26:484-490.
25.Laporte JC,Moode PE,Baraldo S,et a1.Direct effects of inter-leukin-13 on signaliI pathways for physiological responses in cultured human airway smooth muscle cells[J].Am J Respir Crit CareMed,2001,164:141-148.
26.徐振晔,王中奇,朱晏伟.等.肺岩宁对晚期非小细胞肺癌生长转移和血清VEGF的影响[J].上海中医药大学学报,2003,17(1):18-22.
27.张苗,蒋春明,孙净。黄芪对腹膜透析相关腹膜间皮细胞VEGF分泌和表达的影响医学临床研究2005, 22(l2):112-114.
28 Duh E, Aiello LP. Vascular endothelial growth factor and diabetes: the agonist versus antagonist paradox.Diabetes. 1999 Oct;48(10):899-906.
29.Hashimoto M, Tanaka H, Abe S. Quantitative analysis of bronchial wall vascularity in the medium and small airways of patients with asthma and COPD.Chest,2005,127(3):965-972.
30.Asai K, Kanazawa H, Kamoi H, et al. Increased levels of vascular endothelial growth factor induced sputum in asthmatic patients.Clin Exp Allergy,2003,33(5):595 -599.
31.Kazi AS, Lotfi S, Goncharova EA, et al. Vascular endothelial growth factor-induced secretion of fibronectin is ERK dependent.Am J Physiol Lung Cell Mol Physiol,2004,286(3): L539-545.
32.Hirst SJ, Twort CH, Lee TH. Differential effects of extracellular matrix proteins on human airway smooth muscle cell proliferation and phenotype. Am J Respir Cell Mol Biol, 2000,23(3):335-344.
1.钟南山.支气管哮喘一基础与临床,人民卫生出版社,2006,438.
2.刘鑫,戴爱国.黄芪对哮喘豚鼠嗜酸粒细胞凋亡及气道重塑的影响四川中医,2005,23(6):11—12.
3.鲍志坚,徐俭朴,楼景英.黄芪复方对哮喘患者气道高反应性的影响[J].浙江中西医结合杂志,2002,11(2):30—31.
4.苏南湘,张四方,何明大.黄芪注射液为主治疗慢性支气管炎40例[J].湖南医杂志,2003,19(6):30—31.
5.张洁,孙秀珍,田蓉。黄芪对哮喘患者气道反应性的影响第四军医大学学报2006:27(8):701-702.
6.Wen FQ,Kohyama T, Skold CM,et al.Glucocorticoids molecular TGF-beta production by human fetal lung fibroblast[J]. Inflammation,2003, 27(1):9-19.
7.李明才,何韶衡,转化生长因子-β与哮喘,《生命的化学》2003,23(1):57—58.
8.林晓明何建猷梁标,白介素13在哮喘发病机制中的作用,国际病理科学与临床杂志,2005,25(6)539—542.
9. Saez AO, Du T, Wang NS, et al·Methacholine-induced bronchoconstriction and airway smooth muscle in the guinea pig·J ApplPhysiol,1996,80:437-444·
10. JamesAL, ParePD , Hogg JC.The mechanics of airway narrowing in asthma.Am Rev Respir Dis,1989,139:242-246
11. Bramley AM, Thomson RJ, Roberts CR, et al·Excessive bronchoconstriction in asthma is due to decreased airway elastance·Eur Respir J,1994,7:337-341.
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