European Archives of Oto-Rhino-Laryngology

, Volume 269, Issue 1, pp 87–92 | Cite as

Inhibition of fibroblast growth factor receptor 1: influence on tympanic membrane wound healing in rats

  • Holger Kaftan
  • Lars Reuther
  • Bärbel Miehe
  • Werner Hosemann
  • Achim Beule
Otology
First Online:
Received:
Accepted:

Abstract

An animal model of chronic tympanic membrane (TM) perforation is needed for experiments on supporting healing of TM perforations. The basic fibroblast growth factor is important in TM wound healing. The object of this study was to investigate the efficacy of fibroblast growth factor receptor 1 (FGFR1) inhibition to arrest wound healing of experimental TM perforation. Bilateral instrumental myringotomies were performed in 12 rats. A specific inhibitor of the FGFR1 tyrosine kinase (SU5402) was applied to the left TM (2 mg/ml) and to the right TM (10 mg/ml) of each animal daily for 12 consecutive days. Thereafter, TMs were observed weekly for a total of 30 days. TM healing was delayed in a dose-dependent manner. We observed differences in the histologic parameters between both groups. SU 5402 is a strong inhibitor of TM healing but seems not to be suitable to create a chronic TM perforation in rat.

Keywords

FGFR 1 SU5402 Tympanic membrane Myringotomy Wound healing 
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Notes

Acknowledgments

The authors acknowledge Ulrich Stefenelli for his support in the statistical evaluation. Mrs. Wolter and the staff of the Department of Laboratory Animal Science, University of Greifswald, are thanked for expert technical assistance.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Hakuba N, Iwanaga M, Tanaka S, Hiratsuka Y, Kumabe Y, Konishi M, Okanoue Y, Hiwatashi N, Wada T (2010) Basic fibroblast growth factor combined with atelocollagen for closing chronic tympanic membrane perforations in 87 patients. Otol Neurotol 31:118–121PubMedCrossRefGoogle Scholar
  2. 2.
    Kaftan H, Eyrich D, Schindler E, Göpferich A, Hosemann W (2006) Fibrin gel for treatment of tympanic membrane perforations: an experimental animal model. HNO 54:943–946PubMedCrossRefGoogle Scholar
  3. 3.
    Boedts D, Ars B (1977) Histopathological research on eardrum perforations. Arch Otorhinolaryngol 215:55–59PubMedCrossRefGoogle Scholar
  4. 4.
    Kaftan H, Hosemann W, Beule A, Junghans D (2004) An improved animal model for chronic perforation of the tympanic membrane. HNO 52:714–719PubMedGoogle Scholar
  5. 5.
    Mondain M, Ryan A (1995) Epidermal growth factor and basic fibroblast growth factor are induced in guinea-pig tympanic membrane following traumatic perforation. Acta Otolaryngol (Stockh) 115:50–54CrossRefGoogle Scholar
  6. 6.
    Mondain M, Ryan A (1993) Histological study of the healing of traumatic tympanic membrane perforation after basic fibroblast growth factor application. Laryngoscope 103:312–318PubMedCrossRefGoogle Scholar
  7. 7.
    Chellaiah A, Yuan W, Chellaiah M, Ornitz DM (1999) Mapping ligand binding domains in chimeric fibroblast growth factor receptor molecules. Multiple regions determine ligand binding specificity. J Biol Chem 274:34785–34794PubMedCrossRefGoogle Scholar
  8. 8.
    Eswarakumar VP, Lax I, Schlessinger J (2005) Cellular signaling by fibroblast growth factor receptors. Cytokine Growth Factor Rev 16:139–149PubMedCrossRefGoogle Scholar
  9. 9.
    Mohammadi M, McMahon G, Sun L, Tang C, Hirth P, Yeh BK, Hubbard SR, Schlessinger J (1997) Structures of the tyrosine kinase domain of fibroblast growth factor receptor in complex with inhibitors. Science 276:955–960PubMedCrossRefGoogle Scholar
  10. 10.
    Bernard-Pierrot I, Ricol D, Cassidy A, Graham A, Elvin P, Caillault A, Lair S, Broët P, Thiery JP, Radvanyi F (2004) Inhibition of human bladder tumour cell growth by fibroblast growth factor receptor 2b is independent of its kinase activity. Involvement of the carboxy-terminal region of the receptor. Oncogene 23:9201–9211PubMedGoogle Scholar
  11. 11.
    Ishibe T, Nakayama T, Okamoto T, Aoyama T, Nishijo K, Shibata KR, Shima Y, Nagayama S, Katagiri T, Nakamura Y, Nakamura T, Toguchida J (2005) Disruption of fibroblast growth factor signal pathway inhibits the growth of synovial sarcomas: potential application of signal inhibitors to molecular target therapy. Clin Cancer Res 11:2702–2712PubMedCrossRefGoogle Scholar
  12. 12.
    Redmond SL, Levin B, Heel KA, Atlas MD, Marano RJ (2011) Phenotypic and genotypic profile of human tympanic membrane derived cultured cells. J Mol Hist 42:15–25CrossRefGoogle Scholar
  13. 13.
    Fischer H, Taylor N, Allerstorfer S, Grusch M, Sonvilla G, Holzmann K, Setinek U, Elbling L, Cantonati H, Grasl-Kraupp B, Gauglhofer C, Marian B, Micksche M, Berger W (2008) Fibroblast growth factor receptor-mediated signals contribute to the malignant phenotype of non-small cell lung cancer cells: therapeutic implications and synergism with epidermal growth factor receptor inhibition. Mol Cancer Ther 7:3408–3419PubMedCrossRefGoogle Scholar
  14. 14.
    Widberg CH, Newell FS, Bachmann AW, Ramnoruth SN, Spelta MC, Whitehead JP, Hutley LJ, Prins JB (2009) Fibroblast growth factor receptor 1 is a key regulator of early adipogenic events in human preadipocytes. Am J Physiol Endocrinol Metab 296:E121–E131PubMedCrossRefGoogle Scholar
  15. 15.
    Numata Y, Terui T, Okuyama R, Hirasawa N, Sugiura Y, Miyoshi I, Watanabe T, Kuramasu A, Tagami H, Ohtsu H (2006) The accelerating effect of histamine on the cutaneous wound-healing process through the action of basic fibroblast growth factor. J Invest Dermatol 126:1403–1409PubMedCrossRefGoogle Scholar
  16. 16.
    Schmidt SH, Hellström S (1991) Tympanic membrane structure-new views: a comparative study. ORL 53:32–36PubMedCrossRefGoogle Scholar
  17. 17.
    Kaftan H, Herzog M, Miehe B, Hosemann W (2006) Topical application of TGF-β1 in acute traumatic tympanic membrane perforations: an experimental study in rats. Wound Rep Reg 14:453–456CrossRefGoogle Scholar
  18. 18.
    Kaftan H, Reuther L, Miehe B, Hosemann W, Herzog M (2008) Delay of tympanic membrane wound healing in rats with topical application of a tyrosine kinase inhibitor. Wound Rep Reg 16:364–369CrossRefGoogle Scholar
  19. 19.
    Fina M, Baird A, Ryan A (1993) Direct application of basic fibroblast growth factor improves tympanic membrane perforation healing. Laryngoscope 103:804–809PubMedCrossRefGoogle Scholar
  20. 20.
    Lehmann EL (1998) Nonparametrics: Statistical methods based on ranks. New Jersey, Prentice Hall, pp 156–201Google Scholar
  21. 21.
    Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M (2008) Growth factors and cytokines in wound healing. Wound Rep Reg 16:585–601CrossRefGoogle Scholar
  22. 22.
    Mondain M, Renard N, Ryan A (1995) Neutralizing antibodies against basic fibroblast growth factor influence the healing of traumatic tympanic membrane perforations. ORL 57:28–32PubMedCrossRefGoogle Scholar
  23. 23.
    Powers CJ, McLeskey SW, Wellstein A (2000) Fibroblast growth factors, their receptors and signaling. Endocr Relat Cancer 7:165–197PubMedCrossRefGoogle Scholar
  24. 24.
    Kaftan H, Reuther L, Miehe B, Hosemann W, Herzog M (2010) The influence of inhibition of the epidermal growth factor receptor on tympanic membrane wound healing in rats. Growth Factors 28:286–292PubMedCrossRefGoogle Scholar
  25. 25.
    Yamanaka H, Obata K, Kobayashi K, Dai Y, Fukuoka T, Noguchi K (2007) Activation of fibroblast growth factor receptor by axotomy, through downstream p38 in dorsal root ganglion, contributes to neuropathic pain. Neuroscience 150:202–211PubMedCrossRefGoogle Scholar
  26. 26.
    Izikki M, Guignabert C, Fadel E, Humbert M, Tu L, Zadigue P, Dartevelle P, Simonneau G, Adnot S, Maitre B, Raffestin B, Eddahibi S (2009) Endothelial-derived FGF2 contributes to the progression of pulmonary hypertension in humans and rodents. J Clin Invest 119:512–523PubMedCrossRefGoogle Scholar
  27. 27.
    Ramsay HA, Heikkonen EJ, Laurila PK (1995) Effect of epidermal growth factor on tympanic membranes with chronic perforations: a clinical trial. Otolaryngol Head Neck Surg 113:375–379PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • Holger Kaftan
    • 3
    • 1
  • Lars Reuther
    • 1
  • Bärbel Miehe
    • 2
  • Werner Hosemann
    • 1
  • Achim Beule
    • 1
  1. 1.Department of Otorhinolaryngology and Head and Neck SurgeryUniversity of GreifswaldGreifswaldGermany
  2. 2.Department of Anatomy and Cell BiologyUniversity of GreifswaldGreifswaldGermany
  3. 3.Department of Otorhinolaryngology and Head and Neck SurgeryErnst Moritz Arndt UniversityGreifswaldGermany

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