Role of Chemokines in the Pathogenesis of Bleomycin-induced Scleroderma

最近的研究结果表明，趋化因子参与了纤维化过程。我们报道了MCP-1不仅上调胶原蛋白的mRNA表达，而且上调胶原酶和金属蛋白酶-1组织抑制剂（TIMP-1）的mRNA表达（J immunojournal; 2000; 164: 6174-6179）。MCP-1在系统性硬化症（SSc）病变皮肤中被强烈检测到（J Dermatol Sci 2001; 26: 133-139）， MCP-1的自发mRNA表达在硬皮病成纤维细胞中也升高（Eur J Immunol 2001; 31: 2936-2941）。我们先前通过反复注射博来霉素建立了小鼠硬皮病模型，从组织学和生化角度模拟人类硬皮病（J Invest Dermatol 1999; 112: 456-462; J Rheumatol 1999; 26: 2628-2634; Arch Dermatol 2000; 292: 535-541）。在该模型中，博来霉素治疗后，MCP-1及其受体CCR-2在病变皮肤中的表达增强，体内抗MCP-1抗体中和和局部博来霉素治疗减少了真皮硬化的发展。体外数据显示MCP-1上调细胞外基质蛋白mRNA的表达。这些数据提示MCP-1/CCR-2通路在博莱霉素诱导的硬皮病发病机制中起重要作用。

Recent findings suggest the involvement of chemokines in the fibrotic process. We reported that MCP-1 upregulates mRNA expression of not only collagen, but also collagenase and tissue inhibitor of metalloproteinase-1 (TIMP-1) (J Immunol 2000; 164: 6174-6179). MCP-1 was strongly detected in the lesional skin of systemic sclerosis (SSc) (J Dermatol Sci 2001; 26: 133-139), and spontaneous mRNA expression of MCP-1 was also elevated in scleroderma fibroblasts (Eur J Immunol 2001; 31: 2936-2941). We previously established a mouse model for scleroderma by repeated injections of bleomycin, mimicking human scleroderma both histologically and biochemically (J Invest Dermatol 1999; 112: 456-462, J Rheumatol 1999; 26: 2628-2634, Arch Dermatol Res 2000; 292: 535-541). In this model, expression of MCP-1 as well as its receptor, CCR-2, was enhanced in the lesional skin following bleomycin treatment, in vivo neutralization with anti-MCP-1 antibody together with local bleomycin treatment reduced the development of dermal sclerosis. In vitro data demonstrated that MCP-1 upregulates mRNA expression of extracellular matrix proteins. These data suggest MCP-1/CCR-2 pathway plays an important role in the pathogenesis of bleomycin-induced scleroderma.