The Inhibitory Mechanism of Imatinib Mesylate on Bleomycin-Induced Pulmonary Fibrosis in Mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Li ,  LI Yanqin.

Department of Respiratory Medicine, Renji Hospital, Medical College of Shanghai Jiaotong University. Shanghai, 200127, China;

Corresponding author：

LI Yanqin., Email: drliyanqin@126.com

Keywords：

Imatinib mesylate; Pulmonary fibrosis; Bleomycin; α-Smooth muscle actin; Transforming growth factor-

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Objective To explore the inhibitory mechanism of Imatinib mesylate on pulmonary fibrosis induced by bleomycin inmice. Methods A total of 120 C57BL/6 mice were randomly divided into four groups, ie. a control group, a model group, a dexamethasone group, and an Imatinib group. The model of pulmonary fibrosis was established by a single intratracheal instillation of bleomycin in the rats. Then dexamethasone or Imatinib were given intraperitoneally respectively. On day 7, 14, 21 after the treatment, 10 mice of each group were sacrificed respectively. The expressions of TGF-β1 and α-SMA in lung tissue were analyzed by immunohistochemistry. The mRNA expression of TGF-β1 was measured by RT-PCR. Results The expressions of TGF-β1 and α-SMA in lung tissue at each time point were significantly increased in the model group compared with the control group. And the expressions were obviously decreased in the dexamethasone group and the Imatinib group compared with the model group, with no significant differences between the two treatment groups. The expression of TGF-β1 was positively correlated with the α-SMA expression ( r= 0. 251, P lt;0. 05) . Conclusion The inhibitory effect of Imatinib on pulmonary fibrosis may be related to the inhibition of TGF-β1 and α-SMA expressions.

Citation： LI Li,LI Yanqin.. The Inhibitory Mechanism of Imatinib Mesylate on Bleomycin-Induced Pulmonary Fibrosis in Mice. Chinese Journal of Respiratory and Critical Care Medicine, 2009, 09(4): 365-370. doi: Copy

1.	Davies HR, Richeldi L. Idiopathic pulmonary fibrosis: current and future treatment options. Am J Respir Med, 2002, 1: 211-224.
2.	American Thoracic Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment international Consensus statement. Am J Respir Crit Care Med, 2000, 161: 646-664.
3.	Hoyles RK, Du Bois RM. Treatment of idiopathic pulmonary fibrosis: a European perspective Clin Pulm Med, 2006 , 13: 17-24.
4.	Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol, 1999, 155: 213-221.
5.	Dik WA, McAnulty RJ, Versnel MA, et al. Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats. Thorax, 2003, 58: 765-771.
6.	李莉, 李燕芹. 格列卫对博莱霉素致小鼠肺纤维化的干预作用.中国危重病急救医学, 2007, 19: 229-232.
7.	Kolb M,Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med, 2001, 163. : 770-777.
8.	李万成, 刘维佳, 李艳萍, 等. 血管内皮生长因子受体抑制剂SU5416 对小鼠肺间质纤维化的影响. 中国呼吸与危重监护杂志, 2007, 6: 55-58.
9.	Aono Y, Nishioka Y, Inayama M, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.Am J Respir Crit Care Med, 2005, 171: 1279-1285.
10.	陈碧, 张德平. 姜黄素干预对实验性肺间质纤维化的影响. 中国呼吸与危重监护杂志, 2007, 6: 208-213.
11.	Torday JS, Torres E, Rehan VK. The role of fibroblast transdifferentiation in lung epithelial cell proliferation, differentiation and repair in vitro. Pediatr Pathol Mol Med, 2003, 22: 189-207.
12.	Untergasser G, Gander R, Lilg C, et al. Profiling molecular targets of TGF-β1 in prostate fibroblast- to-myofibroblast transdifferentiation.Mech Ageing Dev, 2005, 126: 59-69.
13.	穆茂, 程德云, 杨礼腾, 等. 阿魏酸钠对肺纤维化大鼠肺组织转化生长因子-β1 信号通路分子mRNA 表达的影响. 中国呼吸与危重监护杂志, 2007, 6: 110-113.
14.	黄山英, 宋良文. 效应细胞、细胞因子及相关基因调控在肺纤维化发生中的作用研究进展. 国外医学呼吸系统分册, 2005, 25:328-330.
15.	Shiwen X, Leask A, Denton CP, et al. Transforming growth factorbeta 1 induces endothelin expression by lung fibroblasts: possible role of endothelin in pulmonary fibrosis in scleroderma. BRITISH SOCIETY FOR RHEUMATOLOGY ANNUAL MEETING 19-22 APRIL 2005.
16.	Khalil N, Parekh TV, O’Connor R, et al. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors ( T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Thorax, 2001 , 56 : 907-915.
17.	Phan SH. The myofibroblast in pulmonary fibrosis. Chest, 2002 ,122: 286s-289s.
18.	Zhang HY, Phan SHL. Inhibition of myofibroblast apoptosis by transforming growth factor beta. Am J Respir Cell Mol Biol, 1999 ,21: 658-665.
19.	Abdollahi A, Li M, Ping G, et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med,2005, 21, 201: 925-935.
20.	Supplement 1: i16, March 2005.

1. Davies HR, Richeldi L. Idiopathic pulmonary fibrosis: current and future treatment options. Am J Respir Med, 2002, 1: 211-224.
2. American Thoracic Society. Idiopathic pulmonary fibrosis: Diagnosis and treatment international Consensus statement. Am J Respir Crit Care Med, 2000, 161: 646-664.
3. Hoyles RK, Du Bois RM. Treatment of idiopathic pulmonary fibrosis: a European perspective Clin Pulm Med, 2006 , 13: 17-24.
4. Rice AB, Moomaw CR, Morgan DL, et al. Specific inhibitors of platelet-derived growth factor or epidermal growth factor receptor tyrosine kinase reduce pulmonary fibrosis in rats. Am J Pathol, 1999, 155: 213-221.
5. Dik WA, McAnulty RJ, Versnel MA, et al. Short course dexamethasone treatment following injury inhibits bleomycin induced fibrosis in rats. Thorax, 2003, 58: 765-771.
6. 李莉, 李燕芹. 格列卫对博莱霉素致小鼠肺纤维化的干预作用.中国危重病急救医学, 2007, 19: 229-232.
7. Kolb M,Margetts PJ, Galt T, et al. Transient transgene expression of decorin in the lung reduces the fibrotic response to bleomycin. Am J Respir Crit Care Med, 2001, 163. : 770-777.
8. 李万成, 刘维佳, 李艳萍, 等. 血管内皮生长因子受体抑制剂SU5416 对小鼠肺间质纤维化的影响. 中国呼吸与危重监护杂志, 2007, 6: 55-58.
9. Aono Y, Nishioka Y, Inayama M, et al. Imatinib as a novel antifibrotic agent in bleomycin-induced pulmonary fibrosis in mice.Am J Respir Crit Care Med, 2005, 171: 1279-1285.
10. 陈碧, 张德平. 姜黄素干预对实验性肺间质纤维化的影响. 中国呼吸与危重监护杂志, 2007, 6: 208-213.
11. Torday JS, Torres E, Rehan VK. The role of fibroblast transdifferentiation in lung epithelial cell proliferation, differentiation and repair in vitro. Pediatr Pathol Mol Med, 2003, 22: 189-207.
12. Untergasser G, Gander R, Lilg C, et al. Profiling molecular targets of TGF-β1 in prostate fibroblast- to-myofibroblast transdifferentiation.Mech Ageing Dev, 2005, 126: 59-69.
13. 穆茂, 程德云, 杨礼腾, 等. 阿魏酸钠对肺纤维化大鼠肺组织转化生长因子-β1 信号通路分子mRNA 表达的影响. 中国呼吸与危重监护杂志, 2007, 6: 110-113.
14. 黄山英, 宋良文. 效应细胞、细胞因子及相关基因调控在肺纤维化发生中的作用研究进展. 国外医学呼吸系统分册, 2005, 25:328-330.
15. Shiwen X, Leask A, Denton CP, et al. Transforming growth factorbeta 1 induces endothelin expression by lung fibroblasts: possible role of endothelin in pulmonary fibrosis in scleroderma. BRITISH SOCIETY FOR RHEUMATOLOGY ANNUAL MEETING 19-22 APRIL 2005.
16. Khalil N, Parekh TV, O’Connor R, et al. Regulation of the effects of TGF-beta 1 by activation of latent TGF-beta 1 and differential expression of TGF-beta receptors ( T beta R-I and T beta R-II) in idiopathic pulmonary fibrosis. Thorax, 2001 , 56 : 907-915.
17. Phan SH. The myofibroblast in pulmonary fibrosis. Chest, 2002 ,122: 286s-289s.
18. Zhang HY, Phan SHL. Inhibition of myofibroblast apoptosis by transforming growth factor beta. Am J Respir Cell Mol Biol, 1999 ,21: 658-665.
19. Abdollahi A, Li M, Ping G, et al. Inhibition of platelet-derived growth factor signaling attenuates pulmonary fibrosis. J Exp Med,2005, 21, 201: 925-935.
20. Supplement 1: i16, March 2005.

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