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

博莱霉素诱导的小鼠硬皮病的新治疗方法和分子机制

• 批准号: 22591079
• 负责人: YAMAMOTO Toshiyuki
• 金额: $ 2.91万
• 依托单位: Fukushima Medical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22591079/
• 关键词: 膠原病; 強皮症; 皮膚硬化; 線維化; 抗線維化; ブレオマイシン; 治療

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.

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。

项目成果

Discoid lupus erythematosus in a patient with scleroderma and hepatitis C virus infection.

硬皮病和丙型肝炎病毒感染患者的盘状红斑狼疮。

• 发表时间: 2010
• 期刊: Rheumatol Int
• 影响因子: 4
• 作者: Yamamoto M;Yamamoto T;Tsuboi R
• 通讯作者: Tsuboi R

TGF-beta pathobiology in murine scleroderma

小鼠硬皮病中的 TGF-β 病理学

• 发表时间: 2010
• 作者: Yamamoto T;et. al.
• 通讯作者: et. al.

全身性強皮症に伴う全身症状(皮膚科膠原病診療のすべて)

与系统性硬皮病相关的全身症状（所有关于皮肤胶原病治疗）

• 发表时间: 2011
• 作者: Fujita N; et al;山本俊幸
• 通讯作者: 山本俊幸

Endothelin receptor antagonist bosentan improves the dermal sclerosis in a patient with systemic sclerosis.

内皮素受体拮抗剂波生坦可改善系统性硬化症患者的皮肤硬化。

• 发表时间: 2012
• 期刊: Australas J Dermatol
• 影响因子: 2
• 作者: Nishibu A;Sakai E;Oyama N;Yamamoto T.
• 通讯作者: Yamamoto T.

Prevention of excessive collagen accumulation by human intravenous immunoglobulin treatment in a murine model of bleomycin-induced scleroderma

• DOI: 10.1111/j.1365-2249.2010.04295.x
• 发表时间: 2011-02-01
• 期刊: CLINICAL AND EXPERIMENTAL IMMUNOLOGY
• 影响因子: 4.6
• 作者: Kajii, M.;Suzuki, C.;Nakae, T.
• 通讯作者: Nakae, T.