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

在本项目中，我们在博莱霉素诱导的小鼠硬皮病模型上观察了舒尼替尼和波生坦的抗纤维化作用。舒尼替尼4 mg/kg/d、40 mg/kg/d口服，每周5次，疗程3周，同时局部应用博莱霉素。皮肤硬化显著减少，真皮厚度、肥大细胞数量和皮肤中的胶原含量也显著减少。相比之下，肺纤维化没有被抑制，这表明博莱霉素对肺和皮肤的敏感性不同。在另一项实验中，口服波生坦(150μg/ml)与博莱霉素联合治疗，可抑制博莱霉素引起的皮肤硬化和毛囊萎缩，抑制皮损中肥大细胞的浸润和脱颗粒。此外，口服波生坦还可抑制α-SMA阳性肌成纤维细胞的迁移，增加E-选择素阴性的血管构筑。这些新药有望对人类硬皮病的治疗有利。

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.