Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Prevent Bleomycin-Induced Lung Fibrosis in Mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LI Weifeng ¹ , LI Li ¹ , YUAN Weifeng ^1,2 , XU Hong ¹ , HUANG Wenjie. ¹

Department of Respiratory Medicine, Guangzhou General Hospital of GuangzhouMilitary Command. Guangzhou, Guangdong,510010, ChinaCorresponding Author: LI Li, E-mail: lili_china@ 163. com;

Corresponding author：

Keywords：

Epidermal growth factor receptor tyrosine kinase inhibitor; Erlotinib; Gefitinib; Lung fibrosis; Bleomycin

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Objective To evaluate the effects of two different epidermal growth factor receptor tyrosine kinase inhibitors ( EGFR-TKIs) , Gefitinib and Erlotinib, on lung fibrosis induced by bleomycin.Methods Forty BALB/c female mice were randomly divided into four groups, ie. a control group( saline given orally and intratracheally) , a fibrosis group( saline given orally with bleomycin instillation) , a Gefitnib group( Gefitnib 20 mg/kg given orally with bleomycin instillation) , and an Erlotinib group ( Erlotinib
25 mg/kg given orally with bleomycin instillation) . Bleomycin ( 3 mg/kg) was intratracheally instilled on the first day. Gefitinib or Erlotinib was given orally daily and normal saline as control. Then they were sacrificed by abdominal aortic bleeding 14 days after the bleomycin instillation. The left lung was stained with HE and Masson’s trichrome staining respectively for pathological examination. Total EGFR and phosphorylated EGFR were detected by immunohistochemistry. Hydroxyproline ( HYP) assay was performed in the right lung.Results Both Gefitinib and Erlotinib significantly reduced lung collagen accumulation and the content of HYP. Immunohistochemistry revealed that phosphorylation of EGFR in lung mesenchymal cells induced by bleomycin was inhibited. Furthermore, there was no difference between Gefitinib and Erlotinib in inhibiting lung fibrosis. Conclusion Our findings suggest that, in the preclinical setting, EGFR-TKIs may have a
protective effect on lung fibrosis induced by bleomycin.

Citation： LI Weifeng,LI Li,YUAN Weifeng,XU Hong,HUANG Wenjie.. Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Prevent Bleomycin-Induced Lung Fibrosis in Mice. Chinese Journal of Respiratory and Critical Care Medicine, 2010, 9(4): 426-429. doi: Copy

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1. Carter CA, Kelly RJ, Giaccone G. Small-molecule inhibitors of the human epidermal receptor family. Expert Opin Investig Drugs,2009, 18: 1829-1842 .
2. Erp NP, Gelderblom H, Guchelaar HJ. Clinical pharmacokinetics of tyrosine kinase inhibitors. Cancer Treat Rev, 2009, 35 : 692-706.
3. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol,1988, 41: 467-470 .
4. 李元桂, 蔡向阳, 车东媛, 等. 肺纤维化大鼠肺内血小板源生长因子受体的表达及黄芪对其的影响. 同济医科大学学报, 2000 ,29( 增刊) : 119 -121.
5. 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.
6. Hardie WD, Le Cras TD, Jiang K, et al. Conditional expression of transforming growth factor-alpha in adult mouse lung causes pulmonary fibrosis. AmJ Physiol Lung Cell Mol Physiol, 2004, 286 :L741-L749 .
7. Nethery DE, Moore BB, Minowada G, et al. Expression of mutant human epidermal receptor 3 attenuates lung fibrosis and improves survival in mice. J Appl Physiol, 2005, 99 : 298-307.
8. Kudoh S, Kato H, Nishiwaki Y, et al. Interstitial lung disease in Japanese patients with lung cancer. Am J Respir Crit Care Med,2008, 177: 1348-1357.
9. Takano T, Ohe Y, Kusumoto M, et al. Risk factors for interstitial lung disease and predictive factors for tumor response in patients with advanced non-small cell lung cancer treated with gefitinib.Lung Cancer, 2004 , 45: 93-104 .
10. Cohen MH, Johnson JR, Chen YF, et al. FDA drug approval summary: elotinib ( Tarceva) tablets. Oncologist, 2005, 10 : 461 -466.
11. Shepherd FA, Rodrigues PJ, Cinleanu T, et al. Erlotinib in previously treaded non-small-cell lung cancer. N Engl J Med, 2005 ,353: 123-132.
12. Lee E, Yi JY, Chung E, et al. Transforming growth factor beta1 transactivates EGFR via an H2 O2 -dependent mechanism in squamous carcinoma cell line. Cancer Letters, 2010, 290: 43-48.

Chinese Journal of Respiratory and Critical Care Medicine

Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors Prevent Bleomycin-Induced Lung Fibrosis in Mice

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