[1]甘文华,黄 凯,吕紫薇,等.吡非尼酮和尼达尼布体外抗肺纤维化作用[J].中国药理学通报,2019,(10):1370-1375.[doi:10.3969/j.issn.1001-1978.2019.10.009]
 GAN Wen-hua,HUANG Kai,LYU Zi-wei,et al.Comparison of in-vitro anti-fibrotic effects of pirfenidone and nintedanib[J].Chinese Pharmacological Bulletin,2019,(10):1370-1375.[doi:10.3969/j.issn.1001-1978.2019.10.009]
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吡非尼酮和尼达尼布体外抗肺纤维化作用()
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《中国药理学通报》[ISSN:/CN:]

卷:
期数:
2019年10期
页码:
1370-1375
栏目:
论著
出版日期:
2019-09-15

文章信息/Info

Title:
Comparison of in-vitro anti-fibrotic effects of pirfenidone and nintedanib
文章编号:
1001-1978(2019)10-1370-06
作者:
甘文华1黄 凯1吕紫薇1高劭妍12苏程程3李霄鹤12周红刚12
1.南开大学药物化学生物学国家重点实验室、南开大学药学院和天津市分子药物研究重点实验室,天津 300350; 2.天津 国际生物医药联合研究院高通量分子筛选中心,天津 300070; 3.中国人民武装警察部队特色医学中心,天津 300162
Author(s):
GAN Wen-hua1HUANG Kai1LYU Zi-wei1GAO Shao-yan12SU Cheng-cheng3LI Xiao-he12 ZHOU Hong-gang12
1.State Key Lab of Medicinal Chemical Biology,College of Pharmacy and Key Lab of Molecular Drug Research,Nankai University, Tianjin 300350,China; 2.High-throughput Molecular Drug Screening Centre,Tianjin International Joint Academy of Biomedicine, Tianjin 300070,China; 3.Chinese Medical Police Force Special Medical Center,Tianjin 300162,China
关键词:
肺纤维化 吡非尼酮 尼达尼布 成纤维细胞 细胞外基质 TGF-β/Smad3信号通路
Keywords:
pulmonary fibrosis pirfenidone nintedanib myofibroblasts extracellular matrix TGF-β/Smad3 signaling pathway
分类号:
R329.24; R563.130.2; R563.130.5; R974
DOI:
10.3969/j.issn.1001-1978.2019.10.009
文献标志码:
A
摘要:
目的 通过评价吡非尼酮、尼达尼布对人胚肺成纤维细胞HFL1增殖、迁移、活化的抑制作用,在细胞层面研究对比现有肺纤维化上市药物的作用机制。方法 通过MTT、划痕、qPCR和蛋白免疫印迹实验,评价吡非尼酮和尼达尼布对TGF-β1/PDGF诱导的HFL1增殖、迁移、活化的抑制作用。结果 MTT、划痕实验结果显示,吡非尼酮和尼达尼布均可抑制TGF-β1诱导的成纤维细胞增殖和迁移,其中尼达尼布效价高于吡非尼酮。抗活化实验中,吡非尼酮和尼达尼布均能抑制成纤维细胞活化标志物mRNA和蛋白的表达,作用相当,且均能抑制Smad3的磷酸化,抑制TGF-β/Smad3信号通路的活化,其中尼达尼布对Smad3磷酸化的抑制率为51%,吡非尼酮对Smad3磷酸化的抑制率为13%,尼达尼布抑制作用强于吡非尼酮。结论 吡非尼酮和尼达尼布均可抑制成纤维细胞的增殖、迁移和活化,其中尼达尼布作用效价高于吡非尼酮,且对TGF-β/Smad3信号通路抑制作用较强。
Abstract:
Aim To compare the mechanism of action of currently marketed pulmonary fibrosis drugs at the cellular level by evaluating the inhibitory effects of pirfenidone and nintedanib on the proliferation,migration and activation of human embryonic lung fibroblast HFL1.Methods The inhibitory effects of pirfenidone and nintedanib on TGF-β1/PDGF-induced HFL1 pro-liferation,migration and activation were evaluation of by MTT,scratch test,Q-PCR and Western blot.Results MTT,scratch test results showed that both pirfenidone and nintedanib could inhibit TGF-β1-induced fibroblast proliferation and migration,in which nintedanib had a higher titer than pirfenidone.In anti-activation experiments,both pirfenidone and nintedanib inhibited the expression of fibroblast activation markers mRNA and protein,and both inhibited the phosphorylation of Smad3 and inhibited the activation of TGF-β/Smad3 signaling pathway.Nintedanib had a stronger inhibitory effect on TGF-β/Smad3 signaling pathway,which exerted 51% inhibitory rate on Smad3 phosphorylation compared with 13% inhibitory rate of pirfenidone.Conclusions Both pirfenidone and nintedanib can inhibit the proliferation,migration and activation of myofibroblasts,where nintedanib has a higher inhibitory potency than pirfenidone does,and the inhibition of TGF-β/Smad3 signaling pathway is stronger.

参考文献/References:

[1] Wynn T A.Integrating mechanisms of pulmonary fibrosis[J].J Exp Med,2011,208(7):1339.
[2] Kim E S,Keating G M.Pirfenidone:a review of its use in idiopathic pulmonary fibrosis[J].Drugs,2015,75(2):219-30.
[3] Pourgholamhossein F,Rasooli R,Pournamdari M,et al.Pirfenidone protects against paraquat-induced lung injury and fibrosis in mice by modulation of inflammation,oxidative stress,and gene expression[J].Food Chem Toxicol,2017,112:39-46.
[4] Iyer S N,Gurujeyalakshmi G,Giri S N.Effects of pirfenidone on procollagen gene expression at the transcriptional level in bleomycin hamster model of lung fibrosis[J].J Pharmacol Exp Ther,1999,291(1):211-8.
[5] Robalo-Cordeiro C,Campos P,Carvalho L,et al.Idiopathic pulmonary fibrosis in the era of antifibrotic therapy:Searching for new opportunities grounded in evidence[J].Rev Port Pneumol,2017,23(5):287-93.
[6] 中华医学会呼吸病学分会间质性肺疾病学组.特发性肺纤维化诊断和治疗中国专家共识[J].中华结核和呼吸杂志,2016,39(6):427-32.
[6] Chinese Medical Association Respiratory Diseases Association Interstitial Pulmonary Diseases Group.Chinese expert consensus on diagnosis and treatment of idiopathic pulmonary fibrosis[J].Chin J Tubere Respir Dis,2016,39(6):427-32.
[7] Kendall R T,Feghali-Bostwick C A.Fibroblasts in fibrosis:novel roles and mediators[J].Front Pharmacol,2014,5(123):123.
[8] 孟 哲,李海禹,陶海龙.基于TGF-β1/Smad3信号通路探讨虾青素对心肌成纤维细胞Ⅰ、Ⅲ型胶原表达的影响[J].中国药理学通报,2018,34(6):841-5.
[8] Meng Z,Li H Y,Tao H L.Effect of astaxanthin on the expression of type I and III collagen in cardiac fibroblasts based on TGF-β1/Smad3 protein signaling pathway[J].Chin Pharmacol Bull,2018,34(6):841-5.
[9] Antoniades H N,Bravo M A,Avila R E,et al.Platelet-derived growth factor in idiopathic pulmonary fibrosis.[J].J Clin Invest,1990,86(4):1055-64.
[10] Fernandez I E,Eickelberg O.The impact of TGF-β on lung fibrosis:from targeting to biomarkers[J].Proc Am Thorac Soc,2012,9(3):111-6.
[11] Ramos C,Montaño M,Garcí Aalvarez J,et al.Fibroblasts from idiopathic pulmonary fibrosis and normal lungs differ in growth rate,apoptosis,and tissue inhibitor of metalloproteinases expression[J].Am J Respir Cell Mol Biol,2001,24(5):591-8.
[12] Hu H H,Chen D Q,Wang Y N,et al.New insights into TGF-β/Smad signaling in tissue fibrosis.[J].Chem Biol Interact,2018,292:76-83.
[13] Zhao J,Shi W,Wang Y L,et al.Smad3 deficiency attenuates bleomycin-induced,pulmonary fibrosis in mice[J].Am J Physiol Lung Cell Mol Physiol,2002,282(3):585-93.
[14] Patel AS,Lin L,Geyer A, et al.Autophagy in idiopathic pulmonary fibrosis[J].PLoS One,2014,3(5):e41394.
[15] Rangarajan S,Kurundkar A,Kurundkar D,et al.Novel mechanisms for the antifibrotic action of nintedanib[J].Am J Respir Cell Mol Biol,2016,54(1):51-9.

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备注/Memo

备注/Memo:
收稿日期:2019-07-16,修回日期:2019-08-19 基金项目:国家重点研发计划(No 2018YFA0507203); 国家重大新药创制科技重大专项(No SQ2018ZX090201); 南开大学中央高校基本科研业务费专项资金(No 63191147,63191357); 南开大学药物化学生物学国家重点实验室开放基金资助(No 2018128) 作者简介:甘文华(1995-),女,硕士生,研究方向:特发性肺纤维化,E-mail:2120171254@mail.nankai.edu.cn; 黄 凯(1995-),男,硕士生,研究方向:特发性肺纤维化,共同第一作者,E-mail:1329056433@qq.com; 李霄鹤(1991-),女,博士,研究方向:肺纤维化机制,通讯作者,E-mail:lixiaohe908@nankai.edu.cn; 周红刚(1980-),男,博士,副教授,硕士生导师,研究方向:特发性肺纤维化,通讯作者,E-mail:honggang.zhou@nankai.edu.cn
更新日期/Last Update: 2019-09-15