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Impaired wound healing in bleomycin-induced murine scleroderma: a new model of wound retardation

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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.

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Acknowledgments

We thank Ms. Ikuyo Yoshino and Ms. Akiko Kuroiwa for their technical assistance. This research was partially supported by a Grant-in-Aid for Scientific Research (C) (No. 20591355) from the Japan Society for the Promotion of Science to RT.

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    Authors and Affiliations

    1. Department of Dermatology, Tokyo Medical University, Tokyo, Japan

      Tatsuo Maeda, Toshiyuki Yamamoto & Ryoji Tsuboi

    2. Department of Dermatology, Fukushima Medical University, Fukushima, Japan

      Toshiyuki Yamamoto

    3. School of Bioscience and Biotechnology, Tokyo University of Technology, Tokyo, Japan

      Toru Imamura

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    1. Tatsuo Maeda
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    2. Toshiyuki Yamamoto
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    3. Toru Imamura
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    4. Ryoji Tsuboi
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    Correspondence to Toshiyuki Yamamoto.

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    T. Maeda and T. Yamamoto equally contributed to this work.

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    Maeda, T., Yamamoto, T., Imamura, T. et al. Impaired wound healing in bleomycin-induced murine scleroderma: a new model of wound retardation. Arch Dermatol Res 308, 87–94 (2016). https://doi.org/10.1007/s00403-015-1614-7

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    • DOI: https://doi.org/10.1007/s00403-015-1614-7

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