Mechanism of TGF-β/Smad Signaling Pathway Regulating Epithelial-mesenchymal Transition in Tracheal Stenosis after Transplantation_Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Authors：

DUANHong-tao , LIUHong-gang , YANXiao-long , ZHANGZhi-pei ,  LIXiao-fei

Department of Thoracic Surgery, Tangdu Hospital, the Fourth Military Medical University, Xi'an 710038, P. R. China;

Corresponding author：

LIXiao-fei, Email: lxffmmu@163.com

Keywords：

Tracheal transplantation; Tracheal stenosis; Epithelial mesenchymal transition; Mechanism

DOI：

10.7507/1007-4848.20160114

Video：

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Abstract Full text Figures/Tables Video References Cited by

Objective To investigate that the TGF- beta/Smad signaling pathway mediated epithelial mesenchymal transition (EMT) in trachea stenosis after transplantation. Methods 180-220 g male rats (n=50) were randomly divided into a control group and an experimental group. no surgical operation rats were in the control group. tracheal transplantation rats (Wistar-SD rat) were in the experimental group. Graft specimens were obtained in rats on 3,7,10,14,35,90 days after operation. HE staining is used to explain the fibrosis degree of tracheal stenosis. The fibrosis degree of tracheal stenosis was detected by calculating the fibrosis rate. Immunohistochemical staining was used to detect transplanted tracheal, such as EMT related molecules E-cadherin, vimentin, alpha-SMA expression, p-Smad2/3 expression and transcription factor ZEB1, Snail1 expression in tracheal graft specimens. Results HE staining showed that the tracheal fibrosis rate of the control group was 0.171±0.020, fibrosis rate was 0.537±0.013 (P < 0.01) on the third day after transplantation. The result of immunohistochemical staining showed that vimentin positive epithelial cells increased significantly (P < 0.05). E-cadherin expression significantly reduced (P < 0.05). Compared with the control group, TGF- beta expression increased (P < 0.05) in the experiment group. Compared with the control group, the expression of p-Smad2/3, the transcription factor ZEB1 and Snail1 significantly increased (P < 0.05) in the experiment group. Conclusion Mechanism of tracheal stenosis may be due to EMT. At the same time, TGF- beta/Smad signaling pathway and transcription factor ZEB1, Snail1 may regulate the EMT.

Citation： DUANHong-tao, LIUHong-gang, YANXiao-long, ZHANGZhi-pei, LIXiao-fei. Mechanism of TGF-β/Smad Signaling Pathway Regulating Epithelial-mesenchymal Transition in Tracheal Stenosis after Transplantation. Chinese Journal of Clinical Thoracic and Cardiovascular Surgery, 2016, 23(5): 485-489. doi: 10.7507/1007-4848.20160114 Copy

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12.	Wang C J, Zhou Z G, Holmqvist A, et al. Survivin expression quantified by Image Pro-Plus compared with visual assessment. J Extracell Vesicles, 2009, 17(6):530-535.
13.	Zhao Y, Steidle JF, Upchurch GR, et al. Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans. J Thorac Cardiovasc Surg, 2013, 145(4):940-947.
14.	Qu N, de Vos P, Schelfhorst M, et al. Integrity of airway epithelium is essential against obliterative airway disease in transplanted rat tracheas. J Heart Lung Transplant, 2005, 24(7):882-890.
15.	Pain M, Bermudez O, Lacoste P, et al. Tissue remodelling in chronic bronchial diseases:from the epithelial to mesenchymal phenotype. Eur Respir Rev, 2014, 23(131):118-130.
16.	Lawrence DA, Branson B, Oliva I, et al. The wonderful world of the windpipe:a review of central airway anatomy and pathology. Can Assoc Radiol J, 2015, 66(1):30-43.
17.	丁士骜,梅举,鲍春荣, 等. 草酰乙酸对心肌缺血再灌注损伤的保护作用及机制研究. 中国胸心血管外科临床杂志, 2016, 23(3):78-82.
18.	Su J, Yin L P, Zhang X, et al. Chronic allograft nephropathy in rats is improved by the intervention of rhein. Nephrol Dial Transplant, 2013, 45(6):2546-2552.
19.	Peinado H, Quintanilla M, Cano A. Transforming growth factor β-1 induces Snail transcription factor in epithelial cell lines. J Biol Chem, 2003, 278(23):21113-21123.
20.	Mamuya F A, Duncan M K. aV integrins and TGF-β-induced EMT:a circle of regulation. J Mol Cell Cardiol, 2012, 16(3):445-455.
21.	Xiong M, Jiang L, Zhou Y, et al. The miR-200 family regulates TGF-1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am J Physiol Renal Physiol, 2012, 302(3):F369-F379.
22.	Fan K, Qiao X, Nie J, et al. Orthotopic and heterotopic tracheal transplantation model in studying obliterative bronchiolitis. Transpl Immunol, 2013, 28(4):170-175.
23.	Gillen J R, Zhao Y, Harris D A, et al. Short-course rapamycin treat-ment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg, 2013, 96(2):464-472.

1. 张思泉,仲崇浩,史宏灿. 组织工程气管再生的研究进展. 中国胸心血管外科临床杂志, 2015, 11(3):257-260.
2. 梁志波,李小飞,刘锟. 同种异体气管移植的研究及展望. 中国组织工程研究与临床康复, 2008, 7(5):929-932.
3. Rich JT, Gullane PJ. Current concepts in tracheal reconstruction. Curr Opin Otolaryngol Head Neck Surg, 2012, 20(4):246-253.
4. 刘星辰,孙飞,史宏灿. 排斥反应在同种异体气管移植物中的研究进展. 中国胸心血管外科临床杂志, 2015, 22(1):71-74.
5. Haag JC, Jungebluth P, Macchiarini P. Tracheal replacement for primary tracheal cancer. Curr Opin Otolaryngol Head Neck Surg, 2013, 21(2):171-177.
6. Delaere PR. Current opinion in pulmonary medicine. Tracheal Transplant, 2012, 18(4):313-320.
7. Kalluri R, Weinberg R A. The basics of epithelial-mesenchymal transition. J Clin Invest, 2009, 119(6):1420-1428.
8. Acloque H, Adams M S, Fishwick K, et al. Epithelial-mesenchymal transitions:the importance of changing cell state in development and disease. J Clin Invest, 2009, 119(6):1438-1449.
9. Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci, 2009, 66(5):773-787.
10. Barrallo-Gimeno A. The Snail genes as inducers of cell movement and survival:implications in development and cancer. Development, 2005, 132(14):3151-3161.
11. Schrepfer S, Deuse T, Hoyt G, et al. Experimental orthotopic tracheal transplantation:The Stanford technique. Microsurgery, 2007, 27(3):187-189.
12. Wang C J, Zhou Z G, Holmqvist A, et al. Survivin expression quantified by Image Pro-Plus compared with visual assessment. J Extracell Vesicles, 2009, 17(6):530-535.
13. Zhao Y, Steidle JF, Upchurch GR, et al. Prevention of the second stage of epithelial loss is a potential novel treatment for bronchiolitis obliterans. J Thorac Cardiovasc Surg, 2013, 145(4):940-947.
14. Qu N, de Vos P, Schelfhorst M, et al. Integrity of airway epithelium is essential against obliterative airway disease in transplanted rat tracheas. J Heart Lung Transplant, 2005, 24(7):882-890.
15. Pain M, Bermudez O, Lacoste P, et al. Tissue remodelling in chronic bronchial diseases:from the epithelial to mesenchymal phenotype. Eur Respir Rev, 2014, 23(131):118-130.
16. Lawrence DA, Branson B, Oliva I, et al. The wonderful world of the windpipe:a review of central airway anatomy and pathology. Can Assoc Radiol J, 2015, 66(1):30-43.
17. 丁士骜,梅举,鲍春荣, 等. 草酰乙酸对心肌缺血再灌注损伤的保护作用及机制研究. 中国胸心血管外科临床杂志, 2016, 23(3):78-82.
18. Su J, Yin L P, Zhang X, et al. Chronic allograft nephropathy in rats is improved by the intervention of rhein. Nephrol Dial Transplant, 2013, 45(6):2546-2552.
19. Peinado H, Quintanilla M, Cano A. Transforming growth factor β-1 induces Snail transcription factor in epithelial cell lines. J Biol Chem, 2003, 278(23):21113-21123.
20. Mamuya F A, Duncan M K. aV integrins and TGF-β-induced EMT:a circle of regulation. J Mol Cell Cardiol, 2012, 16(3):445-455.
21. Xiong M, Jiang L, Zhou Y, et al. The miR-200 family regulates TGF-1-induced renal tubular epithelial to mesenchymal transition through Smad pathway by targeting ZEB1 and ZEB2 expression. Am J Physiol Renal Physiol, 2012, 302(3):F369-F379.
22. Fan K, Qiao X, Nie J, et al. Orthotopic and heterotopic tracheal transplantation model in studying obliterative bronchiolitis. Transpl Immunol, 2013, 28(4):170-175.
23. Gillen J R, Zhao Y, Harris D A, et al. Short-course rapamycin treat-ment preserves airway epithelium and protects against bronchiolitis obliterans. Ann Thorac Surg, 2013, 96(2):464-472.

Chinese Journal of Clinical Thoracic and Cardiovascular Surgery

Mechanism of TGF-β/Smad Signaling Pathway Regulating Epithelial-mesenchymal Transition in Tracheal Stenosis after Transplantation

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