Christner Paul J, Jimenez Sergio A
Division of Rheumatology, Department of Medicine, Jefferson Medical College, Thomas Jefferson University, 233 South 10th Street, Philadelphia, PA 19107, USA.
Curr Opin Rheumatol. 2004 Nov;16(6):746-52. doi: 10.1097/01.bor.0000137893.68929.86.
Animal models have been extremely valuable in contributing to a better understanding of the pathogenesis of systemic sclerosis. Discussed here are recent studies that have examined the molecular pathways and potential therapeutic approaches for systemic sclerosis using animal models.
Reported evidence further indicates that the immune system plays a role in modulating the fibrosis observed in the tight skin-1/+ mouse model for systemic sclerosis. CD19, interleukin-6, and interleukin-4 are involved. The injection of spleen cells into immune-compromised mice resulted in fibrotic, vascular, and immunologic alterations quite similar to those of systemic sclerosis. Transforming growth factor-beta and its signaling pathway (JAK kinase and STAT-6, Smad2/3, and Smad7) appear to play a central role in the development of fibrosis as well as monocyte chemoattractant protein-1, CCR-2, platelet-derived growth factor C, and excessive apoptosis. Viruses were shown to be possible cofactors. The therapeutic agents hepatocyte growth factor and halofuginone were shown to prevent fibrosis in animal models of systemic sclerosis.
The transforming growth factor-beta signaling pathway is a common mechanism of tissue fibrosis in animal models of systemic sclerosis, although numerous additional molecules modulate this pathway or have a direct effect on fibrosis.
动物模型对于更好地理解系统性硬化症的发病机制具有极其重要的价值。本文讨论了近期利用动物模型研究系统性硬化症分子途径和潜在治疗方法的相关研究。
已有证据进一步表明，免疫系统在调节系统性硬化症紧皮-1/+小鼠模型中观察到的纤维化过程中发挥作用。涉及CD19、白细胞介素-6和白细胞介素-4。将脾细胞注射到免疫缺陷小鼠体内会导致与系统性硬化症相似的纤维化、血管和免疫改变。转化生长因子-β及其信号通路（JAK激酶和STAT-6、Smad2/3以及Smad7）似乎在纤维化发展过程中起核心作用，单核细胞趋化蛋白-1、CCR-2、血小板衍生生长因子C以及过度凋亡也起作用。病毒被证明可能是辅助因子。治疗药物肝细胞生长因子和常山酮在系统性硬化症动物模型中显示可预防纤维化。
转化生长因子-β信号通路是系统性硬化症动物模型中组织纤维化的常见机制，尽管有许多其他分子调节该通路或对纤维化有直接影响。
