title: Impaired wound healing in bleomycin-induced murine scleroderma: a new model of wound retardation.
abstract: Bleomycin-induced scleroderma in mice is an established model for human scleroderma. Making use of this, we have established a new model for wound retardation. After inducing dermal sclerosis by local bleomycin treatment in nude mice, a full-thickness wound was made by punch excision on the bleomycin application site. Mice pretreated with bleomycin showed a significant delay in wound closure, as compared with mice pretreated with phosphate-buffered saline. Proliferation of keratinocytes was significantly inhibited and the number of Ki-67-positive keratinocytes was significantly lower in the bleomycin-pretreated skin. Also, the number of CD31-positive blood vessels was markedly reduced in the bleomycin-treated skin. The topical daily application of basic fibroblast growth factor (bFGF) significantly promoted wound closure, while increasing blood vessel formation and reducing transforming growth factor-β and alpha-smooth muscle actin mRNA levels. Furthermore, only two applications of PG-FGF1, a fusion protein of FGF1 with heparan sulfate proteoglycan, overcame the delay in wound closure. Wound delay in this model mainly occurred as a result of decreased vessel formation and keratinocyte migration following bleomycin treatment. It is expected that this model will provide novel insights into the pathogenesis of wound healing and the exploration of possible candidate drugs for refractory or chronic wounds in the clinical setting.
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Maeda
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan. toyamade@fmu.ac.jp.|Department of Dermatology, Fukushima Medical University, Fukushima, Japan. toyamade@fmu.ac.jp.
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Yamamoto
authors.affiliation: School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan.
authors.forename: Toru
authors.initials: T
authors.lastname: Imamura
authors.affiliation: Department of Dermatology, Tokyo Medical University, Tokyo, Japan.
authors.forename: Ryoji
authors.initials: R
authors.lastname: Tsuboi
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism; D000818:Animals; D001761:Bleomycin / Q000009:adverse effects*; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D016220:Fibroblast Growth Factor 1 / Q000494:pharmacology*; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D015603:Keratinocytes / Q000187:drug effects; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D018919:Neovascularization, Physiologic / Q000187:drug effects; D012333:RNA, Messenger / Q000235:genetics; D012594:Scleroderma, Localized / Q000473:pathology*; D016212:Transforming Growth Factor beta / Q000235:genetics / Q000378:metabolism; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000199:Actins; D019812:Heparan Sulfate Proteoglycans; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C544013:alpha-smooth muscle actin, mouse; D016220:Fibroblast Growth Factor 1; D001761:Bleomycin
keywords: Bleomycin; Mouse model; Retardation; Wound; bFGF