Skip to main content

Advertisement

SpringerLink
Log in

The Suppression Effects of Thalidomide on Human Lung Fibroblasts: Cell Proliferation, Vascular Endothelial Growth Factor Release, and Collagen Production

  • Published:
Lung Aims and scope Submit manuscript

Abstract

Background

Expression of transforming growth factor (TGF)-β1 and increases in angiogenesis and deposition of extracellular matrix are the key features of tracheal granulation formation. The aim of this study was to investigate the potential role of thalidomide in preventing granulation tissue formation from the aspect of cellular effects in vitro, including fibroblast proliferation, vascular endothelial growth factor (VEGF) release, and collagen production.

Methods

Human lung fibroblasts were obtained from bronchus and cultured. The effects of thalidomide on cell proliferation, migration, TGF-β1-induced VEGF, and signal pathway were investigated.

Results

Thalidomide (20 μM) not only inhibited cell proliferation after 24 h [fold increase of cell number, 0.85 ± 0.09 vs. 1.47 ± 0.14 (treatment vs. control group); P < 0.01] and 48 h of incubation (0.85 ± 0.10 vs. 1.97 ± 0.12; P < 0.001), it also inhibited cell migration and slowed wound closure at 24 h (P < 0.001). Thalidomide significantly attenuated TGF-β1-induced VEGF expression at both the mRNA and protein levels. Incubation of thalidomide with cells stimulated with TGF-β1 significantly inhibited their production of collagen. Thalidomide inhibited Smad3, STAT3, and subsequent p44/42 kinase phosphorylation.

Conclusion

Thalidomide may inhibit human fibroblast proliferation and it is worthy of further in vivo investigation.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Law JH, Barnhart K, Rowlett W, de la Rocha O, Lowenberg S (1993) Increased frequency of obstructive airway abnormalities with long-term tracheostomy. Chest 104(1):136–138

    Article  PubMed  CAS  Google Scholar 

  2. Liu H, Chen JC, Holinger LD, Gonzalez-Crussi F (1995) Histopathologic fundamentals of acquired laryngeal stenosis. Pediatr Pathol Lab Med 15(5):655–677

    Article  PubMed  CAS  Google Scholar 

  3. Karagiannidis C, Velehorschi V, Obertrifter B, Macha HN, Linder A, Freitag L (2006) High-level expression of matrix-associated transforming growth factor-beta1 in benign airway stenosis. Chest 129(5):1298–1304

    Article  PubMed  CAS  Google Scholar 

  4. Pokharel RP, Maeda K, Yamamoto T, Noguchi K, Iwai Y, Nakamura H, Iijima K (1999) Expression of vascular endothelial growth factor in exuberant tracheal granulation tissue in children. J Pathol 188(1):82–86

    Article  PubMed  CAS  Google Scholar 

  5. Lee YC, Hung MH, Liu LY, Chang KT, Chou TY, Wang YC, Wu YC, Lai CL, Tsai CC, Su KC, Perng DW (2011) The roles of transforming growth factor-beta and vascular endothelial growth factor in the tracheal granulation formation. Pulm Pharmacol Ther 24(1):23–31

    Article  PubMed  CAS  Google Scholar 

  6. Galluccio G, Lucantoni G, Battistoni P, Paone G, Batzella S, Lucifora V, Dello Iacono R (2009) Interventional endoscopy in the management of benign tracheal stenoses: definitive treatment at long-term follow-up. Eur J Cardiothorac Surg 35(3):429–433

    Article  PubMed  Google Scholar 

  7. Ciccone AM, De Giacomo T, Venuta F, Ibrahim M, Diso D, Coloni GF, Rendina EA (2004) Operative and non-operative treatment of benign subglottic laryngotracheal stenosis. Eur J Cardiothorac Surg 26(4):818–822

    Article  PubMed  Google Scholar 

  8. Grillo HC, Donahue DM, Mathisen DJ, Wain JC, Wright CD (1995) Postintubation tracheal stenosis. Treatment and results. J Thorac Cardiovasc Surg 109(3):486–492 discussion 492–483

    Article  PubMed  CAS  Google Scholar 

  9. Rea F, Callegaro D, Loy M, Zuin A, Narne S, Gobbi T, Grapeggia M, Sartori F (2002) Benign tracheal and laryngotracheal stenosis: surgical treatment and results. Eur J Cardiothorac Surg 22(3):352–356

    Article  PubMed  Google Scholar 

  10. Ward RF, April MM (1998) Mitomycin-C in the treatment of tracheal cicatrix after tracheal reconstruction. Int J Pediatr Otorhinolaryngol 44(3):221–226

    Article  PubMed  CAS  Google Scholar 

  11. Shlomi D, Peled N, Shitrit D, Bendayan D, Amital A, Kramer MR (2008) Protective effect of immunosuppression on granulation tissue formation in metallic airway stents. Laryngoscope 118(8):1383–1388

    Article  PubMed  CAS  Google Scholar 

  12. Keifer JA, Guttridge DC, Ashburner BP, Baldwin AS Jr (2001) Inhibition of NF-kappa B activity by thalidomide through suppression of IkappaB kinase activity. J Biol Chem 276(25):22382–22387

    Article  PubMed  CAS  Google Scholar 

  13. Corral LG, Haslett PA, Muller GW, Chen R, Wong LM, Ocampo CJ, Patterson RT, Stirling DI, Kaplan G (1999) Differential cytokine modulation and T cell activation by two distinct classes of thalidomide analogues that are potent inhibitors of TNF-alpha. J Immunol 163(1):380–386

    PubMed  CAS  Google Scholar 

  14. Or R, Feferman R, Shoshan S (1998) Thalidomide reduces vascular density in granulation tissue of subcutaneously implanted polyvinyl alcohol sponges in guinea pigs. Exp Hematol 26(3):217–221

    PubMed  CAS  Google Scholar 

  15. Bartlett JB, Dredge K, Dalgleish AG (2004) The evolution of thalidomide and its IMiD derivatives as anticancer agents. Nat Rev Cancer 4(4):314–322

    Article  PubMed  CAS  Google Scholar 

  16. Strauss RM, Bate J, Nischal KK, Clayton T, Gooi J, Darling JC, Newton-Bishop JA (2006) A child with laryngo-onychocutaneous syndrome partially responsive to treatment with thalidomide. Br J Dermatol 155(6):1283–1286

    Article  PubMed  CAS  Google Scholar 

  17. Moreira AL, Friedlander DR, Shif B, Kaplan G, Zagzag D (1999) Thalidomide and a thalidomide analogue inhibit endothelial cell proliferation in vitro. J Neurooncol 43(2):109–114

    Article  PubMed  CAS  Google Scholar 

  18. Miyata M, Tamura E, Motoki K, Nagata K, Yamazoe Y (2003) Thalidomide-induced suppression of embryo fibroblast proliferation requires CYP1A1-mediated activation. Drug Metab Dispos 31(4):469–475

    Article  PubMed  CAS  Google Scholar 

  19. Fuchida SI, Shimazaki C, Hirai H, Akamatsu S, Yamada N, Uchida R, Okano A, Okamoto M, Inaba T, Taniwaki M (2008) The effects of thalidomide on chemotactic migration of multiple myeloma cell lines. Int J Lab Hematol 30(3):220–229

    Article  PubMed  Google Scholar 

  20. Komorowski J, Jerczynska H, Siejka A, Baranska P, Lawnicka H, Pawlowska Z, Stepien H (2006) Effect of thalidomide affecting VEGF secretion, cell migration, adhesion and capillary tube formation of human endothelial EA.hy 926 cells. Life Sci 78(22):2558–2563

    Article  PubMed  CAS  Google Scholar 

  21. Ashcroft GS, Yang X, Glick AB, Weinstein M, Letterio JL, Mizel DE, Anzano M, Greenwell-Wild T, Wahl SM, Deng C, Roberts AB (1999) Mice lacking Smad3 show accelerated wound healing and an impaired local inflammatory response. Nat Cell Biol 1(5):260–266

    Article  PubMed  CAS  Google Scholar 

  22. Verrecchia F, Chu ML, Mauviel A (2001) Identification of novel TGF-beta/Smad gene targets in dermal fibroblasts using a combined cDNA microarray/promoter transactivation approach. J Biol Chem 276(20):17058–17062

    Article  PubMed  CAS  Google Scholar 

  23. Blobe GC, Schiemann WP, Lodish HF (2000) Role of transforming growth factor beta in human disease. N Engl J Med 342(18):1350–1358

    Article  PubMed  CAS  Google Scholar 

  24. Leask A, Abraham DJ (2004) TGF-beta signaling and the fibrotic response. FASEB J 18(7):816–827

    Article  PubMed  CAS  Google Scholar 

  25. Niu G, Wright KL, Huang M, Song L, Haura E, Turkson J, Zhang S, Wang T, Sinibaldi D, Coppola D, Heller R, Ellis LM, Karras J, Bromberg J, Pardoll D, Jove R, Yu H (2002) Constitutive Stat3 activity up-regulates VEGF expression and tumor angiogenesis. Oncogene 21(13):2000–2008

    Article  PubMed  CAS  Google Scholar 

  26. Bartoli M, Platt D, Lemtalsi T, Gu X, Brooks SE, Marrero MB, Caldwell RB (2003) VEGF differentially activates STAT3 in microvascular endothelial cells. FASEB J 17(11):1562–1564

    PubMed  CAS  Google Scholar 

  27. Bartoli M, Gu X, Tsai NT, Venema RC, Brooks SE, Marrero MB, Caldwell RB (2000) Vascular endothelial growth factor activates STAT proteins in aortic endothelial cells. J Biol Chem 275(43):33189–33192

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank all the staff members who participated in the study, especially our chief laboratory technician, Mrs. Mo-Ci Wu. This work was supported by research grants from Taipei Veterans General Hospital (V99C1-100).

Conflict of interest

None

Author information

Authors and Affiliations

  1. Department of Chest Medicine, Taipei Veterans General Hospital, 201, Section 2, Shih-Pai Road, Taipei, 11217, Taiwan

    Ching-Min Tseng, Yi-Han Hsiao, Vincent Yi-Fong Su, Kang-Cheng Su, Kuo-Ting Chang & Diahn-Warng Perng

  2. Division of Chest Surgery, Taipei Veterans General Hospital, Taipei, Taiwan

    Yu-Chung Wu

  3. School of Medicine, National Yang-Ming University, Taipei, Taiwan

    Yu-Chung Wu & Diahn-Warng Perng

Authors
  1. Ching-Min Tseng
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yi-Han Hsiao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Vincent Yi-Fong Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Kang-Cheng Su
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yu-Chung Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Kuo-Ting Chang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Diahn-Warng Perng
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Diahn-Warng Perng.

Additional information

C.-M. Tseng and Y.-H. Hsiao contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tseng, CM., Hsiao, YH., Su, V.YF. et al. The Suppression Effects of Thalidomide on Human Lung Fibroblasts: Cell Proliferation, Vascular Endothelial Growth Factor Release, and Collagen Production. Lung 191, 361–368 (2013). https://doi.org/10.1007/s00408-013-9477-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00408-013-9477-1

Keywords

Search

Navigation