The role of mTOR signaling pathway in bleomycin-induced pulmonary fibrosis at mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

LIN Yikai ¹ , MA Aiping ² , ZHOU Weiyue ³ , YE Meizhi ⁴ , LAN Wenbin ² ,  LIU Qun ²

1. Department of Respiratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 360001, P. R. China;
2. Department of Imaging Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian 360001, P. R. China;
3. Department of Endocrinology Medicine, The Yunxiao Hospital, Yunxiao, Fujian, 363399, P. R. China;
4. Department of Pathology, The Haicang Hospital, Xiamen, Fujian 360001, P. R. China;

Corresponding author：

LIU Qun, Email: 385653071@qq.com

Keywords：

Pulmonary fibrosis; Bleomycin; mTOR; Extracellular matrix

DOI：

10.7507/1671-6205.201709017

Video：

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ObjectiveTo investigate the mechanism of mTOR signaling pathway in bleomycin (BLM)-induced pulmonary fibrosis in mice.MethodsSixty C57BL/6 mice were randomly divided into a control group and a BLM group. Pulmonary fibrosis model was induced by single intratracheal instillation of bleomycin (2.5 mg/kg) in the BLM group. Similarly, 0.9% saline was instilled directly into the trachea in the control group. Then all mice were sacrificed at 21 days. The lungs were collected for morphometric analysis with HE and Masson staining. The degree of pulmonary fibrosis was evaluated with Ashcroft score. The activity of mTOR signaling pathway was measured by Western blot. The level of collagen1, collagen3 mRNA was assessed with quantitative real time PCR.ResultsThe thickening alveolar septa, accumulation of inflammatory cells, and fibrous obliteration in the BLM group were exhibited predominantly compared with the control group. There was a significant difference in Ashcroft score between the BLM group and the control (P<0.05). Also, the activity of mTOR signaling pathway was up-regulated and the expression of collagen1 mRNA and collagen3 mRNA was increased in the BLM group.ConclusionAberrant activation of mTOR signaling pathway aggravates the pulmonary fibrogenesis.

Citation： LIN Yikai, MA Aiping, ZHOU Weiyue, YE Meizhi, LAN Wenbin, LIU Qun. The role of mTOR signaling pathway in bleomycin-induced pulmonary fibrosis at mice. Chinese Journal of Respiratory and Critical Care Medicine, 2018, 17(2): 178-182. doi: 10.7507/1671-6205.201709017 Copy

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5.	Du R, Xia L, Ning X, et al. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell, 2014, 25(17): 2650-2659.
6.	Qin J, Xie YY, Huang L, et al. Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis. Nephrology (Carlton), 2013, 18(10): 690-699.
7.	马爱平, 高云周, 兰文斌, 等. PI3K/Akt/HIF-1α 信号通路在博来霉素诱导小鼠肺纤维化中的作用机制研究. 中国呼吸与危重监护杂志. 2016, 15(1): 34-38.
8.	Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science, 2013, 340(6136): 1100-1106.
9.	Thoreen CC, Chantranupong L, Keys HR, et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature, 2012, 485(7396): 109-113.
10.	Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol, 1988, 41(4): 467-470.
11.	Ben-Sahra I, Manning BD.mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol, 2017, 45: 72-82.
12.	Kim SG, Buel GR, Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells, 2013, 35(6): 463-73.
13.	Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol, 2013, 15(6): 555-64.
14.	Gao Y, Xu X, Ding K, et al. Rapamycin inhibits transforming growth factor beta1-induced fibrogenesis in primary human lung fibroblasts. Yonsei Med J, 2013, 54(2): 437-444.
15.	Park JS, Park HJ, Park YS, et al. Clinical significance of mTOR, ZEB1, ROCK1 expression in lung tissues of pulmonary fibrosis patients. BMC Pulm Med, 2014, 14: 168.
16.	Madala SK, Thomas G, Edukulla R, et al. p70 ribosomal S6 kinase regulates subpleural fibrosis following transforming growth factor-alpha expression in the lung. Am J Physiol Lung Cell Mol Physiol, 2016, 310(2): 175-186.
17.	Buschhausen L, Kamm M, Arns W, et al. Successful treatment of a severe case of idiopathic pulmonary fibrosis with rapamycin. Med Klin (Munich), 2005, 100(3): 161-164.
18.	Gui YS, Wang L, Tian X, et al. mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis. PLoS One, 2015, 10(9): e0138625.

1. Ley B, Brown KK, Collard HR. Molecular biomarkers in idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol, 2014, 307(9): 681-691.
2. Wolters PJ, Collard HR, Jones KD. Pathogenesis of idiopathic pulmonary fibrosis. Annu Rev Pathol, 2014, 9: 157-179.
3. Raghu G, Collard HR, Egan JJ, et al. An official ATS/ERS/JRS/ALAT statement: idiopathic pulmonary fibrosis: evidence-based guidelines for diagnosis and management. Am J Respir Crit Care Med, 2011, 183(6): 788-824.
4. Lu Y, Azad N, Wang L, et al. Phosphatidylinositol-3-kinase/Akt regulates bleomycin-induced fibroblast proliferation and collagen production. Am J Respir Cell Mol Biol, 2010, 42(4): 432-441.
5. Du R, Xia L, Ning X, et al. Hypoxia-induced Bmi1 promotes renal tubular epithelial cell-mesenchymal transition and renal fibrosis via PI3K/Akt signal. Mol Biol Cell, 2014, 25(17): 2650-2659.
6. Qin J, Xie YY, Huang L, et al. Fluorofenidone inhibits nicotinamide adeninedinucleotide phosphate oxidase via PI3K/Akt pathway in the pathogenesis of renal interstitial fibrosis. Nephrology (Carlton), 2013, 18(10): 690-699.
7. 马爱平, 高云周, 兰文斌, 等. PI3K/Akt/HIF-1α 信号通路在博来霉素诱导小鼠肺纤维化中的作用机制研究. 中国呼吸与危重监护杂志. 2016, 15(1): 34-38.
8. Bar-Peled L, Chantranupong L, Cherniack AD, et al. A Tumor suppressor complex with GAP activity for the Rag GTPases that signal amino acid sufficiency to mTORC1. Science, 2013, 340(6136): 1100-1106.
9. Thoreen CC, Chantranupong L, Keys HR, et al. A unifying model for mTORC1-mediated regulation of mRNA translation. Nature, 2012, 485(7396): 109-113.
10. Ashcroft T, Simpson JM, Timbrell V. Simple method of estimating severity of pulmonary fibrosis on a numerical scale. J Clin Pathol, 1988, 41(4): 467-470.
11. Ben-Sahra I, Manning BD.mTORC1 signaling and the metabolic control of cell growth. Curr Opin Cell Biol, 2017, 45: 72-82.
12. Kim SG, Buel GR, Blenis J. Nutrient regulation of the mTOR complex 1 signaling pathway. Mol Cells, 2013, 35(6): 463-73.
13. Dibble CC, Manning BD. Signal integration by mTORC1 coordinates nutrient input with biosynthetic output. Nat Cell Biol, 2013, 15(6): 555-64.
14. Gao Y, Xu X, Ding K, et al. Rapamycin inhibits transforming growth factor beta1-induced fibrogenesis in primary human lung fibroblasts. Yonsei Med J, 2013, 54(2): 437-444.
15. Park JS, Park HJ, Park YS, et al. Clinical significance of mTOR, ZEB1, ROCK1 expression in lung tissues of pulmonary fibrosis patients. BMC Pulm Med, 2014, 14: 168.
16. Madala SK, Thomas G, Edukulla R, et al. p70 ribosomal S6 kinase regulates subpleural fibrosis following transforming growth factor-alpha expression in the lung. Am J Physiol Lung Cell Mol Physiol, 2016, 310(2): 175-186.
17. Buschhausen L, Kamm M, Arns W, et al. Successful treatment of a severe case of idiopathic pulmonary fibrosis with rapamycin. Med Klin (Munich), 2005, 100(3): 161-164.
18. Gui YS, Wang L, Tian X, et al. mTOR Overactivation and Compromised Autophagy in the Pathogenesis of Pulmonary Fibrosis. PLoS One, 2015, 10(9): e0138625.

Chinese Journal of Respiratory and Critical Care Medicine

The role of mTOR signaling pathway in bleomycin-induced pulmonary fibrosis at mice

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