Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy
Date
2016
Authors
Cameron, A.
Turner, C.
Adams, D.
Jackson, J.
Melville, E.
Arkell, R.
Anderson, P.
Cowin, A.
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Journal article
Citation
British Journal of Dermatology, 2016; 174(4):786-794
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A.M. Cameron, C.T. Turner, D.H. Adams, J.E. Jackson, E. Melville, R.M. Arkell, P.J. Anderson and A.J. Cowin
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Abstract
Background: Hypertrophic scarring carries a large burden of disease, including disfigurement, pain and disability. There is currently no effective medical treatment to reduce or prevent hypertrophic scarring. Flightless I (Flii), a member of the gelsolin family of actin remodelling proteins, is an important negative regulator of wound repair. Objectives: The objective of this study was to investigate the role of Flii as a potential regulator of hypertrophic scarring. Methods: Using human skin samples and an animal model of bleomycin-induced hypertrophic scarring in mice that overexpress or have reduced expression of Flii, we investigated its effect on dermal fibrosis and hypertrophic scarring. Results: Flii expression was increased in human burns and hypertrophic scars. A similar increase in Flii was observed in hypertrophic scars formed in mice post-treatment with bleomycin. However, Flii-deficient (Flii+/−) mice had reduced scarring in response to bleomycin evidenced by decreased dermal thickness, smaller cross-sectional scar areas, fewer myofibroblasts and a decreased collagen I/III ratio. In contrast, bleomycin-treated Flii-overexpressing mice (FliiTg/Tg) showed increased scar dermal thickness, larger cross-sectional scar areas, more myofibroblasts and an increased collagen I/III ratio. Injecting developing scars with a Flii neutralizing antibody led to a significant reduction in the size of the scars and a reduction in the collagen I/III ratio. Conclusion: This study identifies Flii as a profibrotic agent that contributes to excessive scar formation. Reducing its activity using neutralizing antibodies is a promising approach for reducing hypertrophic scarring.
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© 2015 British Association of Dermatologists