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Reply: A Novel Murine Model of Hypertrophic Scarring Using Subcutaneous Infusion of Bleomycin

Cameron, Alexander M. M.B.B.S., B.Med.Sci.

Plastic and Reconstructive Surgery: July 2014 - Volume 134 - Issue 1 - p 164e
doi: 10.1097/PRS.0000000000000257

Centre for Regenerative Medicine, Mawson Institute, Building V, University of South Australia Mawson Lakes Campus, Mawson Lakes Boulevard, Mawson Lakes, South Australia 5095, Australia,

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I thank Sacak et al. for their considered response to the article entitled “A Novel Murine Model of Hypertrophic Scarring Using Subcutaneous Infusion of Bleomycin.” The rationale behind our murine model is to recreate the pathologic process underlying hypertrophic scarring by using bleomycin infusion to stimulate dermal fibroproliferation. Bleomycin is an antibiotic, originally isolated from Streptomyces verticillus and widely used as an anticancer treatment.1 Bleomycin hydrolase inactivates bleomycin by hydrolyzing the amide bond in the b-amino alanine amide moiety. However, the lack (or shortage) of this enzyme in the lungs and the skin allows bleomycin-induced fibrosis and sclerosis to occur in these organs in a dose-dependent manner.2 Bleomycin was first used to create animal models of pulmonary fibrosis, before Yamamoto and colleagues established a mouse model of scleroderma using daily subcutaneous injections over a 4-week period.3,4

Bleomycin is known to induce production of reactive oxygen species and cause damage to endothelial and other cells types.5 In addition, bleomycin directly stimulates the profibrotic transforming growth factor-β pathway, and a range of other proinflammatory and profibrotic mediators such as chemoattractant protein 1, platelet-derived growth factor, interleukin-4, interleukin-6, and interleukin-13.5 In this way, bleomycin causes scarring by direct activation of inflammatory and fibrotic mediators that have been shown to be important to the development of human hypertrophic scarring.

Regarding the reference by Sacak et al. to the fate of the fibroproliferative changes of the skin, my colleagues and I reported that the histopathologic changes consistent with hypertrophic present after 28 days of bleomycin treatment were still evident at day 56, 28 days after the cessation of bleomycin treatment. However, inflammatory changes, such as epidermal acanthosis, transforming growth factor-β1 expression, and myofibroblast numbers were significantly decreased in the 56-day model compared with the 28-day model. Therefore, we concluded that for testing therapies directed at dampening the inflammatory response that drives fibroproliferation, the 28-day model would be most appropriate. For therapies intended to increase scar remodeling, the 56-day model would potentially be useful. The exact dose scheduling would be determined by the therapy in question.

I agree that there are other valid animal models, such as the rabbit ear model.6,7 Obviously, trials using other animal species will restrict access to transgenic animals, which are of great utility in wound healing research. Furthermore, I believe that the utility of the bleomycin model is that it restricts the research focus to a pathologic process (fibroproliferation) rather than trying to reproduce a pathologic condition unique to humans. I contend that this approach will yield more relevant data about the key mechanism underlying hypertrophic scarring than existing animal models that attempt to reproduce the end-stage disease seen in humans at all costs.

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The author has no financial interest to declare in relation to the content of this communication.

Alexander M. Cameron, M.B.B.S., B.Med.Sci.

Centre for Regenerative Medicine

Mawson Institute, Building V

University of South Australia Mawson Lakes Campus

Mawson Lakes Boulevard

Mawson Lakes, South Australia 5095, Australia

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1. Umezawa H.. Bleomycin (in Japanese). Gan No Rinsho. 1967;13:735
2. Muggia FM, Louie AC, Sikic BI. Pulmonary toxicity of antitumor agents. Cancer Treat Rev. 1983;10:221–243
3. Yamamoto T, Takagawa S, Katayama I, et al. Animal model of sclerotic skin. I: Local injections of bleomycin induce sclerotic skin mimicking scleroderma. J Invest Dermatol. 1999;112:456–462
4. Moseley PL, Hemken C, Hunninghake GW.. Augmentation of fibroblast proliferation by bleomycin. J Clin Invest. 1986;78:1150–1154
5. Yamamoto T, Nishioka K.. Cellular and molecular mechanisms of bleomycin-induced murine scleroderma: Current update and future perspective. Exp Dermatol. 2005;14:81–95
6. Davidson JM.. Animal models for wound repair. Arch Dermatol Res. 1998;290(Suppl):S1–11
7. Atiyeh BS, Hayek SN, Gunn SW.. New technologies for burn wound closure and healing: Review of the literature. Burns. 2005;31:944–956
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