«上一篇/Previous Article|本期目录/Table of Contents|下一篇/Next Article»

《中华肺部疾病杂志》[ISSN:1006-6977/CN:61-1281/TN]

卷:

期数:

2022年03期

页码:

331-334

栏目:

论著

出版日期:

2022-06-20

文章信息/Info

Title:

Iguratimod decreases bleomycin-induced pulmonary fibrosis in association with inhibition of TNF-α in mice

作者:

蔡欣诺; 邵思琪; 马 华; 周冬梅; 潘 彬; 殷松楼

221002 江苏,徐州医科大学附属医院风湿免疫科

Author(s):

Cai Xinnuo;  Shao Siqi;  Ma Hua;  Zhou Dongmei;  Pan Bin;  Yin Songlou.

Department of Rheumatology and Immunology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, China

关键词:

艾拉莫德;  间质性肺病;  肿瘤坏死因子-α;  上皮间充质转化

Keywords:

Iguratimod;  Interstitial lung disease;  Tumor necrosis factor-α;  Epithelial mesenchymal transformation

分类号:

R734.2

DOI:

10.3877/cma.j.issn.1674-6902.2022.03.009

摘要:

目的 观察艾拉莫德(IGU)对博来霉素(BLM)诱导的小鼠间质性肺病(ILD),分析艾拉莫德治疗ILD有效性和作用机制。方法 C57/BL6小鼠随机分为5组:空白对照组(Normal组)、间质性肺病组(BLM组)、艾拉莫德治疗组(BLM+IGU组)、TNF-α组(BLM+TNF-α组)、TNF-α+艾拉莫德治疗组(BLM+TNF-α+IGU组); 建模后BLM+IGU组和BLM+TNF-α+IGU组予90 mg/kg IGU灌胃,BLM+TNF-α组和BLM+TNF-α+IGU组腹腔注射重组鼠肿瘤坏死因子-α(rmTNF-α),每只200 ng; 于第28天处死小鼠; 观察小鼠体重变化; Masson染色观察肺组织病理改变; Western blot法检测相关标志物蛋白表达水平。结果 BLM+TNF-α组小鼠体重较BLM组降低(P<0.05),BLM+TNF-α+IGU组小鼠体重较BLM+TNF-α组上升(P<0.05); Masson染色发现BLM+TNF-α组肺部胶原沉积较BLM组增多,纤维化评分升高,胶原面积增加(P均<0.05); BLM+TNF-α+IGU组胶原沉积较BLM+TNF-α组明显减少(P<0.05); BLM+TNF-α组α-SMA、MMP-2、Vimentin蛋白表达水平较BLM组升高,E-cadherin蛋白表达水平降低(P<0.05); BLM+TNF-α+IGU组较BLM+TNF-α组α-SMA、MMP-2、Vimentin蛋白表达水平降低,E-cadherin蛋白表达水平升高(P<0.05)。结论 艾拉莫德可能通过抑制TNF-α和上皮间充质转化,减轻博来霉素引起的间质性肺病。

Abstract:

Objective To investigate the impact of iguratimod(IGU)on bleomycin-induced interstitial lung disease and the related tumor necrosis factor-α(TNF-α)signaling pathway in mice to explored the effectiveness and possible mechanism of IGU in treating ILD. Methods Construction ILD model. C57/BL6 mice were randomly divided into 5 groups: Normal group, BLM group, BLM+IGU group, BLM+TNF-α group, BLM+TNF-α+IGU group. After the model was established,mice reveived 0.5% CMC-Na or IGU(90 mg/kg, gavage). Some BLM-treated mice were injected intra-peritoneally with PBS or recombinant murine TNF-α(200 ng per mouse)twice a week. The mice were sacrificed at day 28. Observe the change of body weight. Observe the pathological changes of lung tissue by Masson staining. Western blot was used to detect protein levels of related markers. Results Compared with the BLM group, the weight of the mice in BLM+TNF-α group decreased(P<0.05), and the weight of mice in IGU treatment group higher than in BLM+TNF-α group(P<0.05). Compared with the BLM group, Masson staining indicated increased collagen deposition increased in BLM+TNF-α group(P<0.05), while collagen deposition in BLM+TNF-α+IGU group decreased compared with BLM+TNF-α group(P<0.05). Compared with the BLM group, the protein levels of α-SMA, MMP-2, and Vimentin in the BLM+TNF-α group increased, but E-cadherin protein level decreased(P<0.05), which were reversed by concurrent use of IGU(P<0.05). Conclusion IGU can regulate inflammation by inhibiting of TNF-α and EMT, and relieve interstitial lung disease caused by bleomycin.

参考文献/References:

1 Kolb M, Vasakova M. The natural history of progressive fibrosing interstitial lung diseases[J]. Respir Res, 2019, 20(1): 57.
2 Mathai SC, Danoff SK. Management of interstitial lung disease associated with connective tissue disease[J]. BMJ, 2016, 352: h6819.
3 Li J, Bao J, Zeng J, et al. Iguratimod: a valuable remedy from the Asia Pacific region for ameliorating autoimmune diseases and protecting bone physiology[J]. Bone Res, 2019, 7: 27.
4 Li CH, Ma ZZ, Jian LL, et al. Iguratimod inhibits osteoclastogenesis by modulating the RANKL and TNF-alpha signaling pathways[J]. Int Immunopharmacol, 2021, 90: 107219.
5 Yan Q, Du F, Huang X, et al. Prevention of immune nephritis by the small molecular weight immunomodulator iguratimod in MRL/lpr mice[J]. PLoS One, 2014, 9(10): e108273.
6 Wu YX, Sun Y, Ye YP, et al. Iguratimod prevents ovariectomy induced bone loss and suppresses osteoclastogenesis via inhibition of peroxisome proliferator activated receptorγ[J]. Mol Med Rep, 2017, 16(6): 8200-8208.
7 Zhao L, Mu B, Zhou R, et al. Iguratimod ameliorates bleomycin-induced alveolar inflammation and pulmonary fibrosis in mice by suppressing expression of matrix metalloproteinase-9[J]. Int J Rheum Dis, 2019, 22(4): 686-694.
8 Lin H, Wu C, Zhu F, et al. Anti-fibrotic effect of iguratimod on pulmonary fibrosis by inhibiting the fibroblast-to-myofibroblast transition[J]. Adv Med Sci, 2020, 65(2): 338-347.
9 Richeldi L, Collard HR, Jones MG. Idiopathic pulmonary fibrosis[J].Lancet, 2017, 389(10082): 1941-1952.
10 Nieto MA, Huang RY, Jackson RA, et al. EMT: 2016[J]. Cell, 2016, 166(1): 21-45.
11 Kamitani S, Yamauchi Y, Kawasaki S, et al. Simultaneous stimulation with TGF-β1 and TNF-α induces epithelial mesenchymal transition in bronchial epithelial cells[J]. Int Arch Allergy Immunol, 2011, 155(2): 119-128.
12 Mitchell JP, Carmody RJ. NF-kappa B and the transcriptional control of inflammation[J]. Int Rev Cell Mol Biol, 2018, 335: 41-84.
13 Kim HJ, Litzenburger BC, Cui X, et al. Constitutively active type I insulin-like growth factor receptor causes transformation and xenograft growth of immortalized mammary epithelial cells and is accompanied by an epithelial-to-mesenchymal transition mediated by NF-kappaB and snail[J]. Mol Cell Biol, 2007, 27(8): 3165-3175.
14 Fujimoto H, D'Alessandro-Gabazza CN, Palanki MS, et al. Inhibition of nuclear factor-kappaB in T cells suppresses lung fibrosis[J]. Am J Respir Crit Care Med, 2007, 176(12): 1251-60.
15 Carrington R, Jordan S, Pitchford S C, et al. Use of animal models in IPF research[J]. Pulm Pharmacol Ther, 2018, 51: 73-78.
16 Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale[J]. J Clin Pathol, 1988, 41(4): 467-470.
17 Mira-Avendano I, Abril A, Burger CD, et al. Interstitial lung disease and other pulmonary manifestations in connective tissue diseases[J]. Mayo Clin Proc, 2019, 94(2): 309-325.
18 Jiang H, Gao H, Wang Q, et al. Molecular mechanisms and clinical application of Iguratimod: A review[J]. Biomed Pharmacother, 2020, 122: 109704.
19 Heukels P, Moor CC, von der Thüsen JH, et al. Inflammation and immunity in IPF pathogenesis and treatment[J]. Respir Med, 2019, 147: 79-91.
20 Hou J, Ma T, Cao H, et al. TNF-α-induced NF-κB activation promotes myofibroblast differentiation of LR-MSCs and exacerbates bleomycin-induced pulmonary fibrosis[J]. J Cell Physiol, 2018, 233(3): 2409-2419.
21 Pilling D, Vakil V, Cox N, et al. TNF-α-stimulated fibroblasts secrete lumican to promote fibrocyte differentiation[J]. Proc Natl Acad Sci U S A, 2015, 112(38): 11929-11934.
22 Kim KK, Kugler MC, Wolters PJ, et al. Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix[J]. Proc Natl Acad Sci U S A, 2006, 103(35): 13180-13185.
23 Li CW, Xia W, Huo L, et al. Epithelial-mesenchymal transition induced by TNF-α requires NF-κB-mediated transcriptional upregulation of Twist1[J]. Cancer Res, 2012, 72(5): 1290-1300.
24 Markopoulos GS, Roupakia E, Marcu KB, et al. Epigenetic regulation of inflammatory cytokine-induced epithelial-to-mesenchymal cell transition and cancer stem cell generation[J]. Cells, 2019, 8(10): 1143.
25 Wu Y, Deng J, Rychahou PG, et al. Stabilization of snail by NF-kappaB is required for inflammation-induced cell migration and invasion[J]. Cancer Cell, 2009, 15(5): 416-428.
26 Chua HL, Bhat-Nakshatri P, Clare SE, et al. NF-kappaB represses E-cadherin expression and enhances epithelial to mesenchymal transition of mammary epithelial cells: potential involvement of ZEB-1 and ZEB-2[J]. Oncogene, 2007, 26(5): 711-724.
27 Li Y, Zhu G, Zhai H, et al. Simultaneous stimulation with tumor necrosis factor-α and transforming growth factor-β1 induces epithelial-mesenchymal transition in colon cancer cells via the NF-κB pathway[J]. Oncol Lett, 2018, 15(5): 6873-6880.

备注/Memo

备注/Memo:

基金项目: 徐州市科技计划项目(KC16SH11)
通信作者: 殷松楼, Email: caixinnuo@126.com

常用功能

更新日期/Last Update: 2022-06-20