Yamamoto T, Takagawa S, Katayama I, Yamazaki K, Hamazaki Y, Shinkai H, Nishioka K
Department of Dermatology, Tokyo Medical and Dental University, School of Medicine, Japan.
J Invest Dermatol. 1999 Apr;112(4):456-62. doi: 10.1046/j.1523-1747.1999.00528.x.
We have established a mouse model for scleroderma induced by repeated local injections of bleomycin (BLM). Daily injection of BLM at a dose of >10 microg per ml for 4 wk induced histologic changes of dermal sclerosis, but not fibrosis, with thickened and homogenous collagen bundles and cellular infiltrates in BALB/C mice, whereas clinical signs of scleroderma were not apparent. In addition, lung fibrosis was also induced preceding the cutaneous changes. Sclerotic changes were not found in other sites of the skin distant from the injection site. Dermal sclerosis could also be induced by injecting BLM only every other day. The sclerotic changes of the dermis were sustained after ceasing BLM applications for at least 6 wk. Mast cells gradually increased in number as the sclerotic changes developed. Marked degranulation of mast cells was observed with elevated histamine release. The amount of hydroxyproline in skin was significantly increased at 4 wk of BLM treatment as compared with that in untreated or phosphate-buffered saline-treated mice. Anti-nuclear antibody was detected in serum of BLM-treated mice. Transforming growth factor-beta1 mRNA was detected at an early phase, while transforming growth factor-beta2 mRNA was strongly expressed at 4 wk when the sclerotic features were prominent. These results suggest that dermal sclerosis induced by BLM closely resembles systemic sclerosis both histologically and biochemically. Our mouse model can provide a powerful tool of inducing dermal sclerosis to examine the pathogenesis and the therapeutic approach of scleroderma.
我们通过反复局部注射博来霉素（BLM）建立了硬皮病小鼠模型。在BALB/C小鼠中，每天以>10微克/毫升的剂量注射BLM，持续4周，可诱导真皮硬化的组织学改变，但无纤维化，表现为胶原束增厚且均匀，伴有细胞浸润，而硬皮病的临床症状并不明显。此外，在皮肤改变之前也诱导出了肺纤维化。在远离注射部位的皮肤其他部位未发现硬化改变。每隔一天注射BLM也可诱导真皮硬化。停止应用BLM后，真皮硬化改变至少持续6周。随着硬化改变的发展，肥大细胞数量逐渐增加。观察到肥大细胞明显脱颗粒，组胺释放增加。与未治疗或磷酸盐缓冲盐水处理的小鼠相比，BLM治疗4周时皮肤中羟脯氨酸含量显著增加。在BLM治疗的小鼠血清中检测到抗核抗体。早期检测到转化生长因子-β1 mRNA，而在4周时硬化特征明显时，转化生长因子-β2 mRNA强烈表达。这些结果表明，BLM诱导的真皮硬化在组织学和生化方面与系统性硬化非常相似。我们的小鼠模型可为研究硬皮病的发病机制和治疗方法提供一个诱导真皮硬化的有力工具。
