Antinozzi Cristina, Sgrò Paolo, Marampon Francesco, Caporossi Daniela, Del Galdo Francesco, Dimauro Ivan, Di Luigi Luigi
Unit of Endocrinology, Department of Movement, Human and Health Sciences, University of Rome "Foro Italico", 00135 Rome, Italy.
Department of Radiotherapy, Sapienza University of Rome, 00185 Rome, Italy.
Biology (Basel). 2021 May 31;10(6):491. doi: 10.3390/biology10060491.
Oxidative stress plays a key role in systemic sclerosis (SSc) pathogenesis, and an altered redox homeostasis might be responsible for abnormal inflammatory status, fibrosis and tissue damage extension. In this study, we explored the effect of the phosphodiesterase type 5 inhibitor sildenafil in modulating the activation of the CXCL-9, -10, -11/CXCR3 axis, which is fundamental in the perpetuation of inflammation in different autoimmune diseases, in the cell culture of SSc human dermal fibroblasts exposed to a pro-oxidant environment. We observed that sildenafil significantly reduced gene expression and release of CXCL-9, -10 and -11, inhibited the CXCR3 action and suppressed the activation of STAT1-, JNK- and p38MAPK pathways. This in vitro study on dermal fibroblasts supports clinical studies to consider the efficacy of sildenafil in preventing tissue damage and fibrosis in SSc by targeting central biomarkers of disease progression, vascular injuries and fibrosis and reducing the pro-inflammatory activation induced by oxidative stress.
氧化应激在系统性硬化症（SSc）发病机制中起关键作用，氧化还原稳态的改变可能是异常炎症状态、纤维化和组织损伤扩展的原因。在本研究中，我们探讨了5型磷酸二酯酶抑制剂西地那非在暴露于促氧化环境的SSc人皮肤成纤维细胞培养中，对CXCL-9、-10、-11/CXCR3轴激活的调节作用，该轴在不同自身免疫性疾病的炎症持续中起重要作用。我们观察到西地那非显著降低了CXCL-9、-10和-11的基因表达和释放，抑制了CXCR3的作用，并抑制了STAT1、JNK和p38MAPK途径的激活。这项对皮肤成纤维细胞的体外研究支持临床研究考虑西地那非通过靶向疾病进展、血管损伤和纤维化的核心生物标志物以及减少氧化应激诱导的促炎激活来预防SSc组织损伤和纤维化的疗效。
