博莱霉素
医学
纤维化
肌成纤维细胞
促炎细胞因子
趋化因子
免疫学
肺纤维化
单克隆抗体
病理
癌症研究
炎症
抗体
化疗
内科学
作者
Xiao Švec,Hana Štorkánová,Thuong Trinh-Minh,Manh Cuong Tran,Lenka Štorkánová,Hana Hulejová,Sabína Oreská,Barbora Heřmánková,Radim Bečvář,Karel Pavelka,Jiří Vencovský,Jörg Klingelhöfer,Rizwan I Hussain,Jonas Hallén,Ladislav Šenolt,Jörg H W Distler,Michal Tomčík
出处
期刊:Rheumatology
[Oxford University Press]
日期:2023-06-14
卷期号:63 (3): 817-825
被引量:2
标识
DOI:10.1093/rheumatology/kead295
摘要
Our previous studies have demonstrated that the Damage Associated Molecular Pattern (DAMP) protein, S100A4, is overexpressed in the involved skin and peripheral blood of patients with SSc. It is associated with skin and lung involvement, and disease activity. By contrast, lack of S100A4 prevented the development of experimental dermal fibrosis. Herein we aimed to evaluate the effect of murine anti-S100A4 mAb 6B12 in the treatment of preestablished experimental dermal fibrosis.The effects of 6B12 were assessed at therapeutic dosages in a modified bleomycin-induced dermal fibrosis mouse model by evaluating fibrotic (dermal thickness, proliferation of myofibroblasts, hydroxyproline content, phosphorylated Smad3-positive cell count) and inflammatory (leukocytes infiltrating the lesional skin, systemic levels of selected cytokines and chemokines) outcomes, and transcriptional profiling (RNA sequencing).Treatment with 7.5 mg/kg 6B12 attenuated and might even reduce pre-existing dermal fibrosis induced by bleomycin as evidenced by reduction in dermal thickness, myofibroblast count and collagen content. These antifibrotic effects were mediated by the downregulation of TGF-β/Smad signalling and partially by reducing the number of leukocytes infiltrating the lesional skin and decrease in the systemic levels of IL-1α, eotaxin, CCL2 and CCL5. Moreover, transcriptional profiling demonstrated that 7.5 mg/kg 6B12 also modulated several profibrotic and proinflammatory processes relevant to the pathogenesis of SSc.Targeting S100A4 by the 6B12 mAb demonstrated potent antifibrotic and anti-inflammatory effects on bleomycin-induced dermal fibrosis and provided further evidence for the vital role of S100A4 in the pathophysiology of SSc.
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