SILDENAFIL IMPROVES THE REDOX HOMEOSTASIS AND PRO-INFLAMMATORY ACTIVATION IN SYSTEMIC SCLEROSIS FIBROBLASTS EXPOSED TO REACTIVE OXYGEN SPECIES

Oxidative stress plays a key role in systemic sclerosis (SSc) pathogenesis and an altered redox-state could be responsible for abnormal inflammatory status, fibrosis and tissue damage. Emerging evidences highlight the beneficial effects of sildenafil, a phosphodiesterase type 5 inhibitor (PDE5i), in protecting different cell lines from cell damage induced by reactive oxygen species (ROS). The purpose of this study was to evaluate the sensitivity of SSc dermal fibroblasts to an oxidative insult and the ability for sildenafil to influence redox homeostasis, cytotoxicity, as well as cell proliferation and cell cycle progression due to ROS action. Additionally, we evaluated its effect on the activation of pro-inflammatory response, fundamental in the perpetuation of oxidative stress-related inflammation in different autoimmune diseases. We demonstrated that SSc fibroblasts have an increased sensitivity to a pro-oxidant environment in comparison to healthy controls. The sildenafil treatment counteracted the negative effects of ROS on cell viability and proliferation, promoting the activity of specific enzymes involved in redox homeostasis maintenance (i.e., GSH/GSSG and MnSOD). Moreover, this PDE5i exerts an inhibitory effect on gene expression and release into the culture medium of selected cytokines (IL6 and IL8) and chemokines (CXCL9, CXCL10, and CXCL11), by interfering with the activation of upstream pro-inflammatory pathways, such as STAT1, STAT3, JNK, ERK, PKB/AKT and p38MAPK, involved in their expression and release. This in vitro study demonstrates, for the first time, that sildenafil administration prevents ROS-induced instability in human dermal fibroblasts isolated by SSc patients. These results support clinical studies to consider the efficacy of sildenafil in the 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. Keywords: systemic sclerosis; oxidative stress; inflammation; PDE5 inhibitors; chemokines