New therapeutic approach and molecular mechanisms of bleomycin-induced murine scleroderma

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In this project, we examined the anti-fibrotic effects of sunitinib and bosentan in bleomycin-induced murine scleroderma model. Sunitinib (4mg/kg/day, 40 mg/kg/day) was orally administered 5 times per week for 3 weeks, along with local bleomycin treatment. Dermal sclerosis was significantly reduced, as well as dermal thickness, mast cell number, and collagen contents in the skin. By contrast, lung fibrosis was not suppressed, suggesting difference of susceptibility of bleomycin between lung and skin. In another experiment, oral bosentan (150μg/ml) was applied along with bleomycin treatment.Oral bosentan inhibited dermal sclerosis and follicular atrophy caused by bleomycin injection,infiltration and degranulation of mast cells in lesional skin. Also, oral bosentan inhibited migration of α-SMA-positive myofibroblasts with increase of E-selectin-negative vasculature in bleomycin-injected skin. Those new medicines are expected to be favorable for the treatment of human scleroderma.