Effect of mast cell chymase inhibitor on the development of scleroderma in tight-skin mice
Effect of mast cell chymase inhibitor on the development of scleroderma in tight-skin mice
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DOI：
10.1038/sj.bjp.0706209
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发表时间：
2005-06-01
影响因子：
7.3
通讯作者：
Okunishi, H
中科院分区：
文献类型：
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作者：
Shiota, N;Kakizoe, E;Okunishi, H
1虽然硬皮病的发病机制尚未完全了解，但结缔组织型肥大细胞（CTMCs）的激活与各种纤维化疾病有关。2我们先前的研究表明，在硬皮病模型（即皮肤紧绷（Tsk）小鼠）的皮肤纤维增生期间，CTMCs的数量显著增加。由于肥大细胞表达多种生物活性因子，如细胞因子、生长因子、蛋白酶等，因此确定可能参与硬皮病发病机制的主要因素至关重要。我们之前的研究还表明，CTMC特异性蛋白酶，糜蛋白酶-4，根据皮肤纤维化的发展在Tsk小鼠中选择性上调。3为了进一步阐明CTMC分泌的糜蛋白酶的作用，我们评估了合成糜蛋白酶特异性抑制剂SUN-C8257对Tsk小鼠皮肤纤维化发展的治疗作用。SUN-C8257通过腹膜内注射给予13周龄的Tsk小鼠（50 mg/kg/天），持续2周。4用SUN-C8257处理显著降低了43%的糜酶活性和47%的糜酶-4 mRNA水平，并且与注射赋形剂的Tsk小鼠相比，Tsk小鼠的皮下纤维层厚度也降低了42%。5此外，免疫组织化学分析显示，用SUN-C8257处理显著降低了Tsk皮肤纤维层中的转化生长因子（TGF）-β 1染色。这种糜酶抑制剂可以阻止激活纤维组织中潜伏的TGF-β 1的糜酶依赖性途径，并可能表现出抑制纤维化发展的有益作用。6总之，我们的结果强烈支持CTMC来源的糜酶可能在硬皮病发病机制中发挥关键作用的假设。
1 Although the pathogenesis of scleroderma is not fully understood, activation of connective-tissue-type mast cells (CTMCs) has been implicated in various fibrotic diseases.2 Our previous study showed that the number of CTMCs was markedly increased during fibrous proliferation in the skin of a scleroderma model, namely tight-skin (Tsk) mice. Because mast cells express numerous bioactive factors, such as cytokines, growth factors, proteases, and others, it is crucial to identify the primary factors that may be involved in the pathogenesis of scleroderma. Our previous study also showed that a CTMC-specific protease, chymase-4, was selectively upregulated in accordance with the development of skin fibrosis in Tsk mice.3 To further elucidate the role of chymase secreted from CTMCs, we evaluated the therapeutic effects of a synthetic chymase-specific inhibitor, SUN-C8257, on the development of skin fibrosis in Tsk mice. SUN-C8257 (50 mg kg(-1) day(-1)) was administered via intraperitoneal injection in 13-week-old Tsk mice for a period of 2 weeks.4 Treatment with SUN-C8257 significantly reduced chymase activity by 43% and the chymase-4 mRNA level by 47%, and also decreased the thickness of the subcutaneous fibrous layer of Tsk mice by 42% compared with that of Tsk mice injected with vehicle.5 Furthermore, immunohistochemical analysis revealed that transforming growth factor (TGF)-beta1 staining in the fibrous layer of Tsk skin was markedly reduced by the treatment with SUN-C8257. This chymase inhibitor may prevent the chymase-dependent pathway that activates the latent TGF-beta1 in fibrous tissue, and may exhibit beneficial effects that inhibit the development of fibrosis.6 In conclusion, our results strongly support the assumption that CTMC-derived chymase may play a key role in the pathogenesis of scleroderma.