The Role of PI3K/Akt/HIF-1αSignaling Pathway in Bleomycin-Induced Pulmonary Fibrosis in Mice_Chinese Journal of Respiratory and Critical Care Medicine

Authors：

MaAiping ¹ , GaoYunzhou ² , LanWenbin ¹ , QuYuejin ¹ ,  LiuQun ¹

1. Department of Respiratory Medicine, The First Affiliated Hospital of Xiamen University, Xiamen, Fujian, 360001, China;
2. ;

Corresponding author：

LiuQun, Email: 385653071@qq.com

Keywords：

Pulmonary fibrosis; Bleomycin; Hypoxia induced factor-1α; Surfactant protein C

DOI：

10.7507/1671-6205.2016009

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate the role of PI3K/Akt/HIF-1αsignaling pathway in bleomycin-induced pulmonary fibrosis in mice. Methods Fifty-six C57BL/6 mice were randomly divided into a control group and a bleomycin (BLM) group.The pulmonary fibrosis model was induced by single intratracheal instillation of BLM(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 on 21^st day.The lungs were collected for morphometric analysis with HE and Masson staining.The degree of pulmonary fibrosis was evaluated with Ashcroft score and content of hydroxyproline.The activity of PI3K/Akt/HIF-1αsignaling pathway and pro-surfactant protein C (Pro-SPC) were measured by Western blot.The level of collagen3 mRNA was assessed with quantitative real time PCR analysis.Collagen3 protein and numbers of apoptosis cells were observed with immuno-histochemistry. Results It was exhibited that the thickening alveolar septa, accumulation of inflammatory cells, and fibrous obliteration in the BLM group but not in the control group.There was a significant difference in Ashcroft score and hydryoproline content in the BLM group.Meanwhile, the activity of PI3K/Akt/HIF-1αsignaling pathway was up-regulated and the protein of Pro-SPC was decreased in the BLM group.It was revealed that the numbers of apoptosis cells, expressions of Collagen3 protein and mRNA were increased in the BLM group. Conclusion Aberrant activity of PI3K/Akt/HIF-1αsignaling pathway may aggravate the pulmonary fibrogenesis.

Citation： MaAiping, GaoYunzhou, LanWenbin, QuYuejin, LiuQun. The Role of PI3K/Akt/HIF-1αSignaling Pathway in Bleomycin-Induced Pulmonary Fibrosis in Mice. Chinese Journal of Respiratory and Critical Care Medicine, 2016, 15(1): 34-38. doi: 10.7507/1671-6205.2016009 Copy

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3.	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, 25:2650-2659.
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7.	Courtnay R, Ngo DC, Malik N, et al. Cancer metabolism and the Warburg effect:the role of HIF-1 and PI3K.Mol Biol Rep, 2015, 42:841-851.
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10.	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.
11.	Niemi H, Honkonen K, Korpisalo P, et al.HIF-1αand HIF-2αinduce angiogenesis and improve muscle energy recovery.Eur J Clin Invest, 2014, 44:989-999.
12.	Huang SW, Kao JK, Wu CY, et al.Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.Oncotarget, 2014, 5:1363-1381.
13.	Eurlings IM, Reynaert NL, van den Beucken T, et al.Cigarette smoke extract induces a phenotypic shift in epithelial cells; involvement of HIF1αin mesenchymal transition.PLoS One, 2014, 9:e107757.
14.	Jiao M, Nan KJ.Activation of PI3 kinase/Akt/HIF-1alpha pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. Int J Oncol, 2012, 40:461-468.
15.	Raja R, Kale S, Thorat D, et al.Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis.Oncogene, 2014, 17, 33:2053-2064.
16.	王瑞兰, 唐雪, 吴欣, 等.缺氧诱导因子1α与百草枯中毒致急性肺损伤早期肺纤维化的关系.中华劳动卫生职业病杂志, 2012, 30:273-277.
17.	黄赛, 王瑞兰, 陆伦根.缺氧诱导因子1α在急性肺损伤中的作用.中国呼吸与危重监护杂志, 2015, 14:114-117.
18.	穆灵敏, 闫晓晓, 张光谋, 等.大鼠心肌肥厚中磷酸化磷脂酞肌醇3-激酶和磷酸化蛋白激酶B蛋白表达与心肌纤维化的关系.解剖学杂志, 2014, 37:296-299.
19.	唐琳, 郭青, 张翠翠, 等.缺氧诱导因子1α介导的信号通路在血管紧张素Ⅱ诱导肾间质纤维化中的作用.肾脏病杂志, 2011, 3:194-197.
20.	Ketko AK, Donn SM. Surfactant-associated proteins:structure, function and clinical implications. Curr Pediatr Rev, 2014, 10:162-167.
21.	Yang J, Wheeler SE, Velikoff M, et al.Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins.Am J Pathol, 2013, 183:1559-1570.
22.	Sakai N, Tager AM.Fibrosis of two:Epithelial cell-fibroblast interactions in pulmonary fibrosis.Biochim Biophys Acta, 2013, 1832:911-921.

1. 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, 183:788-824.
2. 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, 42:432-441.
3. 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, 25:2650-2659.
4. 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, 18:690-699.
5. 相炜宏, 王立锋, 苗运博, 等.博来霉素诱导小鼠肺纤维化模型的差异基因表达谱分析.中国呼吸与危重监护杂志, 2015, 14:242-249.
6. Zhang J, Guo H, Zhu JS, et al.Inhibition of phosphoinositide 3-kinase/Akt pathway decreases hypoxia inducible factor-1αexpression and increases therapeutic efficacy of paclitaxel in human hypoxic gastric cancer cells.Oncol Lett, 2014, 7:1401-1408.
7. Courtnay R, Ngo DC, Malik N, et al. Cancer metabolism and the Warburg effect:the role of HIF-1 and PI3K.Mol Biol Rep, 2015, 42:841-851.
8. Carnero A, Paramio JM. The PTEN/PI3K/AKT pathway in vivo, cancer mouse models. Front Oncol, 2014, 4:252.
9. Nakanishi A, Wada Y, Kitagishi Y, et al.Link between PI3K/AKT/PTEN pathway and NOX protein in diseases. Aging Dis, 2014, 5:203-211.
10. 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.
11. Niemi H, Honkonen K, Korpisalo P, et al.HIF-1αand HIF-2αinduce angiogenesis and improve muscle energy recovery.Eur J Clin Invest, 2014, 44:989-999.
12. Huang SW, Kao JK, Wu CY, et al.Targeting aerobic glycolysis and HIF-1alpha expression enhance imiquimod-induced apoptosis in cancer cells.Oncotarget, 2014, 5:1363-1381.
13. Eurlings IM, Reynaert NL, van den Beucken T, et al.Cigarette smoke extract induces a phenotypic shift in epithelial cells; involvement of HIF1αin mesenchymal transition.PLoS One, 2014, 9:e107757.
14. Jiao M, Nan KJ.Activation of PI3 kinase/Akt/HIF-1alpha pathway contributes to hypoxia-induced epithelial-mesenchymal transition and chemoresistance in hepatocellular carcinoma. Int J Oncol, 2012, 40:461-468.
15. Raja R, Kale S, Thorat D, et al.Hypoxia-driven osteopontin contributes to breast tumor growth through modulation of HIF1α-mediated VEGF-dependent angiogenesis.Oncogene, 2014, 17, 33:2053-2064.
16. 王瑞兰, 唐雪, 吴欣, 等.缺氧诱导因子1α与百草枯中毒致急性肺损伤早期肺纤维化的关系.中华劳动卫生职业病杂志, 2012, 30:273-277.
17. 黄赛, 王瑞兰, 陆伦根.缺氧诱导因子1α在急性肺损伤中的作用.中国呼吸与危重监护杂志, 2015, 14:114-117.
18. 穆灵敏, 闫晓晓, 张光谋, 等.大鼠心肌肥厚中磷酸化磷脂酞肌醇3-激酶和磷酸化蛋白激酶B蛋白表达与心肌纤维化的关系.解剖学杂志, 2014, 37:296-299.
19. 唐琳, 郭青, 张翠翠, 等.缺氧诱导因子1α介导的信号通路在血管紧张素Ⅱ诱导肾间质纤维化中的作用.肾脏病杂志, 2011, 3:194-197.
20. Ketko AK, Donn SM. Surfactant-associated proteins:structure, function and clinical implications. Curr Pediatr Rev, 2014, 10:162-167.
21. Yang J, Wheeler SE, Velikoff M, et al.Activated alveolar epithelial cells initiate fibrosis through secretion of mesenchymal proteins.Am J Pathol, 2013, 183:1559-1570.
22. Sakai N, Tager AM.Fibrosis of two:Epithelial cell-fibroblast interactions in pulmonary fibrosis.Biochim Biophys Acta, 2013, 1832:911-921.

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The Role of PI3K/Akt/HIF-1αSignaling Pathway in Bleomycin-Induced Pulmonary Fibrosis in Mice

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