4.6 Article

Sildenafil Counteracts the In Vitro Activation of CXCL-9, CXCL-10 and CXCL-11/CXCR3 Axis Induced by Reactive Oxygen Species in Scleroderma Fibroblasts

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BIOLOGY-BASEL
卷 10, 期 6, 页码 -

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MDPI
DOI: 10.3390/biology10060491

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chemokines; systemic sclerosis; reactive oxygen species; fibrosis; sildenafil

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  1. Ministero dell'Istruzione, dell'Universita e della Ricerca, Italy [RBSI14D5NX]

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Oxidative stress is crucial in the pathogenesis of systemic sclerosis (SSc), affecting the inflammatory state, fibrosis, and tissue damage. Studies show that the phosphodiesterase type 5 inhibitor sildenafil can reduce the expression and secretion of pro-inflammatory chemokines in dermal fibroblasts of SSc patients.
Simple Summary Systemic sclerosis (SSc) is a complex autoimmune disease characterized by different clinical features and a high risk of mortality due to multi-organ fibrosis. Oxidative stress plays a key role in SSc pathogenesis, and an altered redox state could be responsible for abnormal inflammatory condition, tissue damage and fibrosis. Different pro-inflammatory mediators (cytokines and chemokines) occur from the earlier to the last stage of this disease, but their relationship with clinical findings is still unclear. To this purpose, studies are still required which work to find biomarkers mirroring the disease progression and potential pharmacological targets improving treatment response. In this study, we demonstrated that the vasoactive drug sildenafil, a phosphodiesterase type 5 inhibitor commonly used to treat pulmonary hypertension, reduces the expression and secretion of pro-inflammatory chemokines in dermal fibroblasts isolated from SSc patients exposed to reactive oxygen species. We demonstrated that this effect relies on the ability of sildenafil to interfere with the pro-inflammatory pathways involved in the expression of these molecules and its capacity to counteract the plasma membrane translocation of their specific receptor. These results sustain clinical studies to consider the use of sildenafil in preventing tissue damage and fibrosis in systemic sclerosis by targeting essential biomarkers of disease progression and reducing the oxidative-stress-induced inflammation. 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.

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