Lakos Gabriella, Takagawa Shinsuke, Chen Shu-Jen, Ferreira Ahalia M, Han Gangwen, Masuda Koichi, Wang Xiao-Jing, DiPietro Luisa A, Varga John
Section of Rheumatology, College of Medicine, University of Illinois at Chicago, 900 S. Ashland Avenue, Chicago, IL 60607, USA.
Am J Pathol. 2004 Jul;165(1):203-17. doi: 10.1016/s0002-9440(10)63289-0.
Transforming growth factor-beta (TGF-beta) is a potent stimulus of connective tissue accumulation, and is implicated in the pathogenesis of scleroderma and other fibrotic disorders. Smad3 functions as a key intracellular signal transducer for profibrotic TGF-beta responses in normal skin fibroblasts. The potential role of Smad3 in the pathogenesis of scleroderma was investigated in Smad3-null (Smad3(-/-)) mice using a model of skin fibrosis induced by subcutaneous injections of bleomycin. At early time points, bleomycin-induced macrophage infiltration in the dermis and local TGF-beta production were similar in Smad3(-/-) and wild-type mice. In contrast, at day 28, lesional skin from Smad3(-/-) mice showed attenuated fibrosis, lower synthesis and accumulation of collagen, and reduced collagen gene transcription in situ, compared to wild-type mice. Connective tissue growth factor and alpha-smooth muscle actin expression in lesional skin were also significantly attenuated. Electron microscopy revealed an absence of small diameter collagen fibrils in the dermis from bleomycin-treated Smad3(-/-) mice. Compared to fibroblasts derived from wild-type mice, Smad3(-/-) fibroblasts showed reduced in vitro proliferative and profibrotic responses elicited by TGF-beta. Together, these results indicate that ablation of Smad3 is associated with markedly altered fibroblast regulation in vivo and in vitro, and confers partial protection from bleomycin-induced scleroderma in mice. Reduced fibrosis is due to deregulated fibroblast function, as the inflammatory response induced by bleomycin was similar in wild-type and Smad3(-/-) mice.
转化生长因子-β（TGF-β）是结缔组织积聚的强效刺激因子，与硬皮病和其他纤维化疾病的发病机制有关。Smad3在正常皮肤成纤维细胞中作为促纤维化TGF-β反应的关键细胞内信号转导分子发挥作用。利用皮下注射博来霉素诱导的皮肤纤维化模型，在Smad3基因敲除（Smad3(-/-)）小鼠中研究了Smad3在硬皮病发病机制中的潜在作用。在早期时间点，博来霉素诱导的真皮巨噬细胞浸润和局部TGF-β产生在Smad3(-/-)小鼠和野生型小鼠中相似。相比之下，在第28天，与野生型小鼠相比，Smad3(-/-)小鼠的病变皮肤显示纤维化减轻、胶原蛋白合成和积聚减少以及原位胶原蛋白基因转录降低。病变皮肤中结缔组织生长因子和α-平滑肌肌动蛋白表达也显著减弱。电子显微镜显示，博来霉素处理的Smad3(-/-)小鼠真皮中不存在小直径胶原纤维。与源自野生型小鼠的成纤维细胞相比，Smad3(-/-)成纤维细胞对TGF-β诱导的体外增殖和促纤维化反应减弱。总之，这些结果表明，Smad3的缺失与体内和体外成纤维细胞调节的显著改变有关，并使小鼠对博来霉素诱导的硬皮病具有部分保护作用。纤维化减轻是由于成纤维细胞功能失调，因为博来霉素诱导的炎症反应在野生型和Smad3(-/-)小鼠中相似。
