Effects of transforming growth factor beta on airway remodeling of obese asthmatic mice treated with pirfenidone_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Hongna ¹ , HAN Wei ¹ , SU Yi ¹ ,  TANG Huaping ¹ , ZHAO Lei ²

1. Department of Respiratory Medicine, East Hospital of Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, Shandong 266071, P.R.China;
2. International Clinic of Qingdao Municipal Hospital (Group), Qingdao, Shandong 266071, P.R.China;

Corresponding author：

TANG Huaping, Email: qdthp@126.com

Keywords：

Obesity; Asthma; Remodeling; Pirfenidone; Transforming growth factor beta

DOI：

10.7507/1671-6205.201701037

Video：

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Objective To investigate the effects of transforming growth factor beta (TGF-β) on airway remodeling in obese asthmatic mice and intervention effects of pirfenidone. Methods Seventy-five C57BL/6J mice were randomly divided into five groups, namely a blank control group (group A), an obese group (group B), an obese asthmatic group (group C), a budesonide treatment group (group D) and a pirfenidone treatment group (group E). The mice in the B, C, D, and E groups were fed with high fat diets, then the mice in the C, D, and E groups were sensitized and challenged with ovalbumin (OVA) to establish the model of chronic obese asthma. The mice in group A were fed with normal diets, sensitized and challenged with normal saline. The mice in group D were treated with budesonide (0.5 mg/ml), and the mice in group E were treated with pirfenidone (300 mg/kg). After 4 weeks of treatment, the total number of white cells as well as the percentage of leukocytes, eosinophils, neutrophils and macrophage in bronchoalveolar lavage fluid (BALF) were counted. ELISA and Western blot were used to evaluate the expression of TGF-β. The pathological changes of mice were observed under light microscope by HE and periodic acid-Schiff staining. Meanwhile the remodeling indices were measured including total bronchial wall area (WAt), smooth muscle area (WAm), and bronchial basement membrane perimeter (Pbm). Results The levels of leukocyte and eosinophils in BALF, expression of TGF-β, WAt/Pbm and WAm/Pbm in group C were higher than those in group A, B, D, and E (allP<0.05). The levels of eosinophils in BALF, WAt/Pbm in group E were lower than those in group D (allP<0.05). The level of TGF-β decreased in a sequence of group C>D>E>B>A (allP<0.05). The expression of TGF-β was in a positive correlation with eosinophil percentage in BALF (r=0.79,P<0.01). Conclusions The expression of TGF-β in the airway of obese asthmatic mice is closely related to airway inflammation, airway hyper-secretion and airway remodeling. Pirfenidone can effectively inhibit the expression of TGF-β and improve airway remodeling.

Citation： LI Hongna, HAN Wei, SU Yi, TANG Huaping, ZHAO Lei. Effects of transforming growth factor beta on airway remodeling of obese asthmatic mice treated with pirfenidone. Chinese Journal of Respiratory and Critical Care Medicine, 2017, 16(3): 217-222. doi: 10.7507/1671-6205.201701037 Copy

1.	Umetsu DT. Mechanisms by which obesity impacts upon asthma. Thorax, 2016, 72(2): 174.
2.	Inomata M, Kamio K, Azuma A. Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res, 2014, 15(1): 1-14.
3.	Wang J, Yang Y, Xu J, et al. Pirfenidone inhibits migration, differentiation, and proliferation of human retinal pigment epithelial cells in vitro. Mol Vis, 2013, 19(11): 2626-2635.
4.	Hirano A, Kanehiro A, Ono K, et al. Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge. Am J Respir Cell Mol Biol, 2006, 35(3): 366-377.
5.	Mansoor JK, Decile KC, Giri SN, et al. Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma. Pulm Pharmacol Ther, 2007, 20(6): 660-668.
6.	Durcan PJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. JAMA Neurol, 1988, 45(8): 875-877.
7.	Han W, Li J, Tang HP, et al. Treatment of obese asthma in a mouse model by simvastatin is associated with improving dyslipidemia and decreasing leptin level. Biochem Biophys Res Commun, 2017, 484(2): 396-402.
8.	Chen M, Lv Z, Zhang W, et al. Triptolide suppresses airway goblet cell hyperplasia and Muc5ac expression via NF-κB in a murine model of asthma. Mol Immunol, 2015, 64(1): 99-105.
9.	Dixon AE, Holguin F, Sood A, et al. An official American Thoracic Society Workshop report: obesity and asthma. Proc Am Thorac Soc, 2010, 7(5): 325-335.
10.	韩伟, 陈凯, 唐华平, 等. 肥胖型哮喘小鼠体内氧化应激反应变化及其与气道炎症和重构的关系. 中国呼吸与危重监护杂志, 2011, 10(4): 331-334.
11.	王丽霞, 韩伟, 陈伟, 等. 辛伐他汀对肥胖哮喘小鼠气道炎症和重构的影响. 中华实用诊断与治疗杂志, 2016, 30(5): 435-438.
12.	Taguchi Y, Ebina M, Hashimoto S, et al. Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: extended analysis of phase Ⅲ trial in Japan. Respir Invest, 2015, 53(6): 279-287.
13.	Macías-Barragán J, Sandoval-Rodríguez A, Navarro-Partida J, et al. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair, 2010, 3(1): 16.
14.	Schaefer CJ, Ruhrmund DW, Pan L, et al. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev, 2011, 20(120): 85-97.
15.	Li XZ, Feng JC, Hu CP, et al. Effects of Arkadia on airway remodeling through enhancing TGF-β signaling in allergic rats. Lab Invest, 2010, 90(7): 997-1003.
16.	Sutherland ER, Goleva E, King TS, et al. Cluster analysis of obesity and asthma phenotypes. Plos One, 2012, 7(5): e36631.
17.	Bottoms SE, Howell JE, Reinhardt AK, et al. TGF-β isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. Plos One, 2012, 5(3): e9674.
18.	Halwani R, Al-Muhsen S, Al-Jahdali H, et al. Role of transforming growth factor-beta in airway remodeling in asthma. Am J Respir Cell Mol Biol, 2011, 44(2): 127-133.
19.	Panek M, Pietras T, Fabijan A, et al. The NR3C1 glucocorticoid receptor gene polymorphisms may modulate the TGF-beta mRNA expression in asthma patients. Inflammation, 2015, 38(4): 1479.
20.	Lee HY, Kim IK, Yoon HK, et al. Inhibitory effects of resveratrol on airway remodeling by transforming growth factor-β/smad signaling pathway in chronic asthma model. Allergy Asthma Immunol Res, 2017, 9(1): 25-34.
21.	Jiang K, Chen HB, Wang Y, et al. Changes in interleukin-17 and transforming growth factor beta 1 levels in serum and bronchoalveolar lavage fluid and their clinical significance among children with asthma. Transl Pediatrics, 2013, 2(4): 154-159.
22.	Durrani SR, Viswanathan RK, Busse WW. What effect does asthma treatment have on airway remodeling? Current perspectives. J Allergy Clin Immunol, 2011, 128(3): 439-448.
23.	Takeda Y, Tsujino K, Kijima T, et al. Efficacy and safety of pirfenidone for idiopathic pulmonary fibrosis. Patient Prefer Adherence, 2014, 8(3): 61-70.
24.	方丽萍, 辛晓峰. 支气管哮喘药物治疗对气道重塑的影响. 中华结核和呼吸杂志, 2012, 35(12): 927-929.
25.	Hirota N, Martin JG. Mechanisms of airway remodeling. Chest, 2013, 144(3): 1026-1032.
26.	Kang HS, Rhee CK, Lee HY, et al. Different anti-remodeling effect of nilotinib and fluticasone in a chronic asthma model. Korean J Intern Med, 2016, 31(6): 1150-1158.

1. Umetsu DT. Mechanisms by which obesity impacts upon asthma. Thorax, 2016, 72(2): 174.
2. Inomata M, Kamio K, Azuma A. Pirfenidone inhibits fibrocyte accumulation in the lungs in bleomycin-induced murine pulmonary fibrosis. Respir Res, 2014, 15(1): 1-14.
3. Wang J, Yang Y, Xu J, et al. Pirfenidone inhibits migration, differentiation, and proliferation of human retinal pigment epithelial cells in vitro. Mol Vis, 2013, 19(11): 2626-2635.
4. Hirano A, Kanehiro A, Ono K, et al. Pirfenidone modulates airway responsiveness, inflammation, and remodeling after repeated challenge. Am J Respir Cell Mol Biol, 2006, 35(3): 366-377.
5. Mansoor JK, Decile KC, Giri SN, et al. Influence of pirfenidone on airway hyperresponsiveness and inflammation in a Brown-Norway rat model of asthma. Pulm Pharmacol Ther, 2007, 20(6): 660-668.
6. Durcan PJ, Corbett JJ, Wall M. The incidence of pseudotumor cerebri: population studies in Iowa and Louisiana. JAMA Neurol, 1988, 45(8): 875-877.
7. Han W, Li J, Tang HP, et al. Treatment of obese asthma in a mouse model by simvastatin is associated with improving dyslipidemia and decreasing leptin level. Biochem Biophys Res Commun, 2017, 484(2): 396-402.
8. Chen M, Lv Z, Zhang W, et al. Triptolide suppresses airway goblet cell hyperplasia and Muc5ac expression via NF-κB in a murine model of asthma. Mol Immunol, 2015, 64(1): 99-105.
9. Dixon AE, Holguin F, Sood A, et al. An official American Thoracic Society Workshop report: obesity and asthma. Proc Am Thorac Soc, 2010, 7(5): 325-335.
10. 韩伟, 陈凯, 唐华平, 等. 肥胖型哮喘小鼠体内氧化应激反应变化及其与气道炎症和重构的关系. 中国呼吸与危重监护杂志, 2011, 10(4): 331-334.
11. 王丽霞, 韩伟, 陈伟, 等. 辛伐他汀对肥胖哮喘小鼠气道炎症和重构的影响. 中华实用诊断与治疗杂志, 2016, 30(5): 435-438.
12. Taguchi Y, Ebina M, Hashimoto S, et al. Efficacy of pirfenidone and disease severity of idiopathic pulmonary fibrosis: extended analysis of phase Ⅲ trial in Japan. Respir Invest, 2015, 53(6): 279-287.
13. Macías-Barragán J, Sandoval-Rodríguez A, Navarro-Partida J, et al. The multifaceted role of pirfenidone and its novel targets. Fibrogenesis Tissue Repair, 2010, 3(1): 16.
14. Schaefer CJ, Ruhrmund DW, Pan L, et al. Antifibrotic activities of pirfenidone in animal models. Eur Respir Rev, 2011, 20(120): 85-97.
15. Li XZ, Feng JC, Hu CP, et al. Effects of Arkadia on airway remodeling through enhancing TGF-β signaling in allergic rats. Lab Invest, 2010, 90(7): 997-1003.
16. Sutherland ER, Goleva E, King TS, et al. Cluster analysis of obesity and asthma phenotypes. Plos One, 2012, 7(5): e36631.
17. Bottoms SE, Howell JE, Reinhardt AK, et al. TGF-β isoform specific regulation of airway inflammation and remodelling in a murine model of asthma. Plos One, 2012, 5(3): e9674.
18. Halwani R, Al-Muhsen S, Al-Jahdali H, et al. Role of transforming growth factor-beta in airway remodeling in asthma. Am J Respir Cell Mol Biol, 2011, 44(2): 127-133.
19. Panek M, Pietras T, Fabijan A, et al. The NR3C1 glucocorticoid receptor gene polymorphisms may modulate the TGF-beta mRNA expression in asthma patients. Inflammation, 2015, 38(4): 1479.
20. Lee HY, Kim IK, Yoon HK, et al. Inhibitory effects of resveratrol on airway remodeling by transforming growth factor-β/smad signaling pathway in chronic asthma model. Allergy Asthma Immunol Res, 2017, 9(1): 25-34.
21. Jiang K, Chen HB, Wang Y, et al. Changes in interleukin-17 and transforming growth factor beta 1 levels in serum and bronchoalveolar lavage fluid and their clinical significance among children with asthma. Transl Pediatrics, 2013, 2(4): 154-159.
22. Durrani SR, Viswanathan RK, Busse WW. What effect does asthma treatment have on airway remodeling? Current perspectives. J Allergy Clin Immunol, 2011, 128(3): 439-448.
23. Takeda Y, Tsujino K, Kijima T, et al. Efficacy and safety of pirfenidone for idiopathic pulmonary fibrosis. Patient Prefer Adherence, 2014, 8(3): 61-70.
24. 方丽萍, 辛晓峰. 支气管哮喘药物治疗对气道重塑的影响. 中华结核和呼吸杂志, 2012, 35(12): 927-929.
25. Hirota N, Martin JG. Mechanisms of airway remodeling. Chest, 2013, 144(3): 1026-1032.
26. Kang HS, Rhee CK, Lee HY, et al. Different anti-remodeling effect of nilotinib and fluticasone in a chronic asthma model. Korean J Intern Med, 2016, 31(6): 1150-1158.

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Effects of transforming growth factor beta on airway remodeling of obese asthmatic mice treated with pirfenidone

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