Tuberculosis and Respiratory Diseases

The Korean Academy of Tuberculosis and Respiratory Diseases (대한결핵및호흡기학회)
권호 표지
DOI QR코드

DOI QR Code

Inhibition of Plasminogen Activator Inhibitor-1 Expression in Smoke-Exposed Alveolar Type II Epithelial Cells Attenuates Epithelial-Mesenchymal Transition

  • Song, Jeong-Sup (Department of Internal Medicine, Yeouido St Mary's Hospital, The Catholic University of Korea College of Medicine) ;
  • Kang, Chun-Mi (Department of Internal Medicine, Yeouido St Mary's Hospital, The Catholic University of Korea College of Medicine)
  • Received : 2010.05.26
  • Accepted : 2010.05.28
  • Published : 2011.06.30
Download PDF
⟨ Previous Next ⟩

Abstract

Background: Smoking is a risk factor for idiopathic pulmonary fibrosis (IPF), but the mechanism of the association remains obscure. There is evidence demonstrating that plasminogen activator inhibitor-1 (PAI-1) is involved in the progression of pulmonary fibrosis. This study was to determine whether the administration of small interfering RNA (siRNA) targeting PAI-1 or PAI-1 inhibitor to the cigarette smoking extract (CSE)-exposed rat alveolar type II epithelial cells (ATII cells) limits the epithelial-mesenchymal transition (EMT). Methods: ATII cells were isolated from lung of SD-rat using percoll gradient method and cultured with 5% CSE. The EMT was determined from the ATII cells by measuring the real-time RT PCR and western blotting after the PAI-1 siRNA transfection to the cells and after administration of tiplaxtinin, an inhibitor of PAI-1. The effect of PAI-1 inhibitor was also evaluated in the bleomycin-induced rats. Results: PAI-1 was overexpressed in the smoking exposed ATII cells and was directly associated with EMT. The EMT from the ATII cells was suppressed by PAI-1 siRNA transfection or administration of tiplaxtinin. Signaling pathways for EMT by smoking extract were through the phosphorylation of SMAD2 and ERK1/2, and finally Snail expression. Tiplaxtinin also suppressed the pulmonary fibrosis and PAI-1 expression in the bleomycin-induced rats. Conclusion: Our data shows that CSE induces rat ATII cells to undergo EMT by PAI-1 via SMAD2-ERK1/2-Snail activation. This suppression of EMT by PAI-1 siRNA transfection or PAI-1 inhibitor in primary type II alveolar epithelial cells might be involved in the attenuation of bleomycin-induced pulmonary fibrosis in rats.

Keywords

References

  1. Selman M, King TE, Pardo A; American Thoracic Society; European Respiratory Society; American College of Chest Physicians. Idiopathic pulmonary fibrosis: prevailing and evolving hypotheses about its pathogenesis and implications for therapy. Ann Intern Med 2001;134:136-51. https://doi.org/10.7326/0003-4819-134-2-200101160-00015
  2. Selman M, Pardo A. Role of epithelial cells in idiopathic pulmonary fibrosis: from innocent targets to serial killers. Proc Am Thorac Soc 2006;3:364-72.
  3. Yao HW, Xie QM, Chen JQ, Deng YM, Tang HF. TGF-beta1 induces alveolar epithelial to mesenchymal transition in vitro. Life Sci 2004;76:29-37. https://doi.org/10.1016/j.lfs.2004.06.019
  4. Loskutoff DJ, Quigley JP. PAI-1, fibrosis, and the elusive provisional fibrin matrix. J Clin Invest 2000;106:1441-3. https://doi.org/10.1172/JCI11765
  5. Fogo AB. Mesangial matrix modulation and glomerulosclerosis. Exp Nephrol 1999;7:147-59. https://doi.org/10.1159/000020595
  6. Zhang LP, Takahara T, Yata Y, Furui K, Jin B, Kawada N, et al. Increased expression of plasminogen activator and plasminogen activator inhibitor during liver fibrogenesis of rats: role of stellate cells. J Hepatol 1999;31:703-11. https://doi.org/10.1016/S0168-8278(99)80351-1
  7. Olman MA, Mackman N, Gladson CL, Moser KM, Loskutoff DJ. Changes in procoagulant and fibrinolytic gene expression during bleomycin-induced lung injury in the mouse. J Clin Invest 1995;96:1621-30. https://doi.org/10.1172/JCI118201
  8. Senoo T, Hattori N, Tanimoto T, Furonaka M, Ishikawa N, Fujitaka K, et al. Suppression of plasminogen activator inhibitor-1 by RNA interference attenuates pulmonary fibrosis. Thorax 2010;65:334-40. https://doi.org/10.1136/thx.2009.119974
  9. Cho SH, Tam SW, Demissie-Sanders S, Filler SA, Oh CK. Production of plasminogen activator inhibitor-1 by human mast cells and its possible role in asthma. J Immunol 2000;165:3154-61. https://doi.org/10.4049/jimmunol.165.6.3154
  10. Eitzman DT, McCoy RD, Zheng X, Fay WP, Shen T, Ginsburg D, et al. Bleomycin-induced pulmonary fibrosis in transgenic mice that either lack or overexpress the murine plasminogen activator inhibitor-1 gene. J Clin Invest 1996;97:232-7. https://doi.org/10.1172/JCI118396
  11. Richards RJ, Davies N, Atkins J, Oreffo VI. Isolation, biochemical characterization, and culture of lung type II cells of the rat. Lung 1987;165:143-58. https://doi.org/10.1007/BF02714430
  12. Chapman HA. Epithelial-mesenchymal interactions in pulmonary fibrosis. Annu Rev Physiol 2011;73:413-35. https://doi.org/10.1146/annurev-physiol-012110-142225
  13. Chilosi M, Poletti V, Zamo A, Lestani M, Montagna L, Piccoli P, et al. Aberrant Wnt/beta-catenin pathway activation in idiopathic pulmonary fibrosis. Am J Pathol 2003;162:1495-502. https://doi.org/10.1016/S0002-9440(10)64282-4
  14. Liu Y, Gao W, Zhang D. Effects of cigarette smoke extract on A549 cells and human lung fibroblasts treated with transforming growth factor-beta1 in a coculture system. Clin Exp Med 2010;10:159-67. https://doi.org/10.1007/s10238-009-0081-x
  15. Xiao W, Hsu YP, Ishizaka A, Kirikae T, Moss RB. Sputum cathelicidin, urokinase plasminogen activation system components, and cytokines discriminate cystic fibrosis, COPD, and asthma inflammation. Chest 2005;128:2316-26. https://doi.org/10.1378/chest.128.4.2316
  16. Xu X, Wang H, Wang Z, Xiao W. Plasminogen activator inhibitor-1 promotes inflammatory process induced by cigarette smoke extraction or lipopolysaccharides in alveolar epithelial cells. Exp Lung Res 2009;35:795-805. https://doi.org/10.3109/01902140902912519
  17. Izuhara Y, Takahashi S, Nangaku M, Takizawa S, Ishida H, Kurokawa K, et al. Inhibition of plasminogen activator inhibitor-1: its mechanism and effectiveness on coagulation and fibrosis. Arterioscler Thromb Vasc Biol 2008;28:672-7. https://doi.org/10.1161/ATVBAHA.107.157479
  18. Cano A, Perez-Moreno MA, Rodrigo I, Locascio A, Blanco MJ, del Barrio MG, et al. The transcription factor snail controls epithelial-mesenchymal transitions by repressing E-cadherin expression. Nat Cell Biol 2000;2:76-83. https://doi.org/10.1038/35000025
  19. Batlle E, Sancho E, Franci C, Dominguez D, Monfar M, Baulida J, et al. The transcription factor snail is a repressor of E-cadherin gene expression in epithelial tumour cells. Nat Cell Biol 2000;2:84-9. https://doi.org/10.1038/35000034
  20. Jayachandran A, Konigshoff M, Yu H, Rupniewska E, Hecker M, Klepetko W, et al. SNAI transcription factors mediate epithelial-mesenchymal transition in lung fibrosis. Thorax 2009;64:1053-61. https://doi.org/10.1136/thx.2009.121798
  21. Liu RM. Oxidative stress, plasminogen activator inhibitor 1, and lung fibrosis. Antioxid Redox Signal 2008;10:303-19. https://doi.org/10.1089/ars.2007.1903
  22. Kotani I, Sato A, Hayakawa H, Urano T, Takada Y, Takada A. Increased procoagulant and antifibrinolytic activities in the lungs with idiopathic pulmonary fibrosis. Thromb Res 1995;77:493-504. https://doi.org/10.1016/0049-3848(95)00025-9
  23. Kim JH, Jang YS, Eom KS, Hwang YI, Kang HR, Jang SH, et al. Transtorming growth factor beta1 induces epithelial-to-mesenchymal transition of A549 cells. J Korean Med Sci 2007;22:898-904. https://doi.org/10.3346/jkms.2007.22.5.898
  24. Lange-Sperandio B, Trautmann A, Eickelberg O, Jayachandran A, Oberle S, Schmidutz F, et al. Leukocytes induce epithelial to mesenchymal transition after unilateral ureteral obstruction in neonatal mice. Am J Pathol 2007;171:861-71. https://doi.org/10.2353/ajpath.2007.061199