Two kinds of epidermal growth factor receptor kinase inhibitors prevent bleomycin-induced lung fibrosis by down-regulating expression of oncostatin M in mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

ZHENG Linxin , CHEN Can , MAI Yumei , LI Li ,  LI Weifeng

Department of Respiratory Medicine, Guangzhou General Hospital of Guangzhou Military Command, Guangzhou, Guangdong 510010, P. R. China;

Corresponding author：

LI Weifeng, Email: lwf980622@126.com

Keywords：

Pulmonary fibrosis; Epidermal growth factor receptor kinase inhibitors; Gefitinib; Erlotinib; Oncostatin M

DOI：

10.7507/1671-6205.201712029

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ObjectiveTo study effects of two kinds of epidermal growth factor receptor kinase inhibitors on bleomycin-induced pulmonary fibrosis in mice, and regulation mechanism on oncostatin M (OSM) and downstream signaling pathways.MethodsForty Kunming female mice were randomly divided into a control group, a fibrosis group, a gefitinib group, and an erlotinib group. The mice in the control group were administered with saline aerosol intratracheally. The mice in the fibrosis group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally. The mice in the gefitinib group and the erlotinib group were administered with bleomycin at a dose of 3 mg/kg aerosol intratracheally and then gastrically perfused with gefitinib (20 mg·kg^–1·d^–1) or erlotinib (25 mg·kg^–1·d^–1). All mice accepted computer tomography examination 14 days after the treatment and then were sacrificed, and the lungs were collected for further detection. The lungs were stained with hematoxylin eosin and Masson’s trichrome, examined with Western blot for pathological examination and expressions of α-smooth muscle actin (α-SMA), OSM, Janus kinase 1 (JAK1), phospho-JAK1 (p-JAK1), signal transducers and activators of transcription 3 (STAT3), and phospho-STAT3 (p-STAT3) proteins.ResultsThe pathological injury of the lung in the gefitinib group and the erlotinib group was significantly relieved compared with that in the bleomycin group. The expressions of α-SMA, OSM, p-JAK1/JAK1, and p-STAT3/STAT3 proteins were also significantly reduced. There were no differences between the above-mentioned indexes between the gefitinib group and the erlotinib group.ConclusionsGefitinib and erlotinib can significantly relieve bleomycin-induced pulmonary fibrosis in mice. The underlying mechanism may be involved in inhibiting expression of OSM and downstream JAK/STAT pathways.

Citation： ZHENG Linxin, CHEN Can, MAI Yumei, LI Li, LI Weifeng. Two kinds of epidermal growth factor receptor kinase inhibitors prevent bleomycin-induced lung fibrosis by down-regulating expression of oncostatin M in mice. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(4): 400-406. doi: 10.7507/1671-6205.201712029 Copy

1.	Wilson KC, Raghu G. The 2015 guidelines for idiopathic pulmonary fibrosis: an important chapter in the evolution of the management of patients with IPF. Eur Respir J, 2015, 46(4): 883-886.
2.	Xueli Nan, Chao Xie, Xueyan Yu, Jie Liu.EGFR-TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget, 2017, 8(43): 75712-75726.
3.	William DH, Cynthia D, Machiko I, et al. EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-αinduced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1217-L1225.
4.	Yoshiki Ishii, Sakae Fujimoto, Takeshi Fukuda. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med, 2006, 174(5): 550-556.
5.	李伟峰, 李理, 袁伟锋, 等. 两种表皮生长因子酪氨酸激酶抑制剂对小鼠肺纤维化的干预作用比较. 中国呼吸与危重监护杂志, 2010, 9(4): 426-429.
6.	Canady J, Arndt S, Karrer S, et al. Increased KGF expression promotes fibroblast activation in a double paracrine manner resulting in cutaneous fibrosis. J Invest Dermatol, 2013, 133(3): 647-657.
7.	Hoermann G, Cerny-Reiterer S, Herrmann H, et al. Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms. FASEB J, 2012, 26(2): 894-906.
8.	Pollack V, Sarközi R, Banki Z, et al. Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. Am J Physiol Renal Physiol, 2007, 293(5): F1714-F1726.
9.	Grant SL, Hammacher A, Douglas AM, et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene, 2002, 21(3): 460-474.
10.	Vlaicu P, Mertins P, Mayr T, et al. Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator. BMC Cancer, 2013, 13: 197-209.
11.	Mikawa K, Nishina K, Takao Y, et al. ONO-1714, a nitric oxide synthase inhibitor,attenuates endotoxin-induced acute lung injury in rabbits. Anesth Analg, 2003, 97(6):1751-1755.
12.	Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol, 1998, 41(4):467-470.
13.	Yan L, Song F, Li H, et al. Submicron emulsion of cinnamaldehyde ameliorates bleomycin-induced idiopathic pulmonary fibrosis via inhibition of inflammation, oxidative stress and epithelial-mesenchymal transition. Biomed Pharmacother, 2018, 102: 765-771.
14.	胡萍, 高占成. 博莱霉素致小鼠肺纤维化模型的动态演变及其发生机制. 中国危重病急救医学, 2006, 18(8): 474-478.
15.	郑林鑫, 麦玉梅, 杜海坚, 等. 吉非替尼下调肿瘤抑制素M抑制博莱霉素诱导的小鼠肺纤维化. 免疫学杂志, 2016, 32(3): 22-26.
16.	Nagahama KY, Togo S, Holz O, et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol, 2013, 49(4): 582-591.
17.	Jahani-Asl A, Yin H, Soleimani VD, et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci, 2016, 19(6): 798-806.
18.	Guerriero ML, Dudka A, Underhill-Day N, et al. Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway. BMC Syst Biol, 2009, 3: 40-51.

1. Wilson KC, Raghu G. The 2015 guidelines for idiopathic pulmonary fibrosis: an important chapter in the evolution of the management of patients with IPF. Eur Respir J, 2015, 46(4): 883-886.
2. Xueli Nan, Chao Xie, Xueyan Yu, Jie Liu.EGFR-TKI as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer. Oncotarget, 2017, 8(43): 75712-75726.
3. William DH, Cynthia D, Machiko I, et al. EGF receptor tyrosine kinase inhibitors diminish transforming growth factor-αinduced pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2008, 294(6): L1217-L1225.
4. Yoshiki Ishii, Sakae Fujimoto, Takeshi Fukuda. Gefitinib prevents bleomycin-induced lung fibrosis in mice. Am J Respir Crit Care Med, 2006, 174(5): 550-556.
5. 李伟峰, 李理, 袁伟锋, 等. 两种表皮生长因子酪氨酸激酶抑制剂对小鼠肺纤维化的干预作用比较. 中国呼吸与危重监护杂志, 2010, 9(4): 426-429.
6. Canady J, Arndt S, Karrer S, et al. Increased KGF expression promotes fibroblast activation in a double paracrine manner resulting in cutaneous fibrosis. J Invest Dermatol, 2013, 133(3): 647-657.
7. Hoermann G, Cerny-Reiterer S, Herrmann H, et al. Identification of oncostatin M as a JAK2 V617F-dependent amplifier of cytokine production and bone marrow remodeling in myeloproliferative neoplasms. FASEB J, 2012, 26(2): 894-906.
8. Pollack V, Sarközi R, Banki Z, et al. Oncostatin M-induced effects on EMT in human proximal tubular cells: differential role of ERK signaling. Am J Physiol Renal Physiol, 2007, 293(5): F1714-F1726.
9. Grant SL, Hammacher A, Douglas AM, et al. An unexpected biochemical and functional interaction between gp130 and the EGF receptor family in breast cancer cells. Oncogene, 2002, 21(3): 460-474.
10. Vlaicu P, Mertins P, Mayr T, et al. Monocytes/macrophages support mammary tumor invasivity by co-secreting lineage-specific EGFR ligands and a STAT3 activator. BMC Cancer, 2013, 13: 197-209.
11. Mikawa K, Nishina K, Takao Y, et al. ONO-1714, a nitric oxide synthase inhibitor,attenuates endotoxin-induced acute lung injury in rabbits. Anesth Analg, 2003, 97(6):1751-1755.
12. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol, 1998, 41(4):467-470.
13. Yan L, Song F, Li H, et al. Submicron emulsion of cinnamaldehyde ameliorates bleomycin-induced idiopathic pulmonary fibrosis via inhibition of inflammation, oxidative stress and epithelial-mesenchymal transition. Biomed Pharmacother, 2018, 102: 765-771.
14. 胡萍, 高占成. 博莱霉素致小鼠肺纤维化模型的动态演变及其发生机制. 中国危重病急救医学, 2006, 18(8): 474-478.
15. 郑林鑫, 麦玉梅, 杜海坚, 等. 吉非替尼下调肿瘤抑制素M抑制博莱霉素诱导的小鼠肺纤维化. 免疫学杂志, 2016, 32(3): 22-26.
16. Nagahama KY, Togo S, Holz O, et al. Oncostatin M modulates fibroblast function via signal transducers and activators of transcription proteins-3. Am J Respir Cell Mol Biol, 2013, 49(4): 582-591.
17. Jahani-Asl A, Yin H, Soleimani VD, et al. Control of glioblastoma tumorigenesis by feed-forward cytokine signaling. Nat Neurosci, 2016, 19(6): 798-806.
18. Guerriero ML, Dudka A, Underhill-Day N, et al. Narrative-based computational modelling of the Gp130/JAK/STAT signalling pathway. BMC Syst Biol, 2009, 3: 40-51.

Chinese Journal of Respiratory and Critical Care Medicine

Two kinds of epidermal growth factor receptor kinase inhibitors prevent bleomycin-induced lung fibrosis by down-regulating expression of oncostatin M in mice

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