title: Flightless I is a key regulator of the fibroproliferative process in hypertrophic scarring and a target for a novel antiscarring therapy.
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.
  
  
  OBJECTIVE
  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 (Flii(Tg/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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.|Discipline of Surgery, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: A M
authors.initials: AM
authors.lastname: Cameron
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.
authors.forename: C T
authors.initials: CT
authors.lastname: Turner
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.
authors.forename: D H
authors.initials: DH
authors.lastname: Adams
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.
authors.forename: J E
authors.initials: JE
authors.lastname: Jackson
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.
authors.forename: E
authors.initials: E
authors.lastname: Melville
authors.affiliation: Research School of Biology, College of Medicine, Biology and Environment, Australian National University, Acton, ACT, 2601, Australia.
authors.forename: R M
authors.initials: RM
authors.lastname: Arkell
authors.affiliation: Discipline of Paediatrics, School of Medicine, Faculty of Health Sciences, The University of Adelaide, Adelaide, SA, Australia.
authors.forename: P J
authors.initials: PJ
authors.lastname: Anderson
authors.affiliation: Regenerative Medicine, Future Industries Institute, University of South Australia, Mawson Lakes, SA, 5095, Australia.
authors.forename: A J
authors.initials: AJ
authors.lastname: Cowin
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000633:toxicity; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D001761:Bleomycin / Q000633:toxicity; D002056:Burns / Q000503:physiopathology; D002352:Carrier Proteins; D017439:Cicatrix, Hypertrophic / Q000209:etiology* / Q000517:prevention & control; D003094:Collagen / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008840:Microfilament Proteins / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D058628:Myofibroblasts / Q000502:physiology; D018160:Receptors, Cytoplasmic and Nuclear / Q000172:deficiency / Q000276:immunology / Q000502:physiology*; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1 / Q000378:metabolism
chemical_list: D000903:Antibiotics, Antineoplastic; D057134:Antibodies, Neutralizing; D002352:Carrier Proteins; D003598:Cytoskeletal Proteins; C098179:FLII protein, human; C000609263:FlII protein, mouse; D008840:Microfilament Proteins; D018160:Receptors, Cytoplasmic and Nuclear; D015534:Trans-Activators; D053773:Transforming Growth Factor beta1; D001761:Bleomycin; D003094:Collagen