S100A9通过激活成纤维细胞参与硬皮病皮肤纤维化的机制研究

项目名称： S100A9通过激活成纤维细胞参与硬皮病皮肤纤维化的机制研究

项目编号： No.81501409

项目类型： 青年科学基金项目

立项/批准年度： 2016

项目学科： 医药、卫生

项目作者： 徐雪

作者单位： 南京大学

项目金额： 18万元

中文摘要： 硬皮病是一种以皮肤及多个内脏器官炎症和弥漫性纤维化为特征的自身免疫性疾病，其发病机制一直未明。目前认为硬皮病患者的皮肤纤维化是由于成纤维细胞过度活化导致细胞外基质产生增加所致，成纤维细胞在该病的发病过程中发挥着关键作用。博来霉素可诱导小鼠皮肤发生纤维化，是硬皮病研究领域的经典模型。本课题组将博来霉素诱导性硬皮病鼠皮肤组织进行基因谱芯片扫描，发现S100A9基因表达明显升高；申请人的前期研究进一步发现硬皮病患者血浆和病变皮肤组织中S100A9含量亦显著升高，且体外S100A9可活化肺成纤维细胞。S100A9已被证实有强大的促炎活性，但尚不清楚该因子是否具有致纤维化的功能。本项目将探讨S100A9如何激活人皮肤成纤维细胞，并诱导细胞分泌细胞外基质增多；观察抗S100A9抗体能否缓解硬皮病模型鼠皮肤的纤维化进程，从而为硬皮病寻找新的治疗靶点提供理论依据。

中文关键词： 硬皮病；S100A9；成纤维细胞；晚期糖基化终末产物受体；纤维化

英文摘要： Scleroderma is an autoimmune disease, characterized by progressive fibrosis of skin and internal organs. However, the mechanisms of scleroderma remain unclear. The fibroblasts are considered to be responsible for excessive collagen and other ECM synthesis and deposition that occur in skin fibrosis. The mouse model of scleroderma established by local injections of bleomycin is a classic model in this field. Our previous data found that the skin tissues from bleomycin treated mice had significantly increased expression of S100A9 by using gene expression chips. S100A9 is confirmed to exert pro-inflammatory effects, whether the cytokine has pro-fibrotic function remains unknown. Our previous research showed that the levels of S100A9 were elevated in the plasma and sclerotic skin of scleroderma patients than controls, and the human embryo lung fibroblasts were activated by S100A9 in vitro. The aims of this study are to investigate whether S100A9 can stimulate skin fibroblasts to produce more collagen, to further determine whether S100A9 could aggravate bleomycin induction of sclerotic changes of the mouse skin, to understand whether the sclerotic changes of the mice skin induced by bleomycin can be alleviate using anti-S100A9 antibody and to further study the fibrotic skin of S100A9 knock-out mice induced by bleomycin can be less. This study may provide insight on the treatment of scleroderma.

英文关键词： Scleroderma;S100A9;Fibroblast;RAGE;Fibrosis