Sildenafil Reduces Expression and Release of IL-6 and IL-8 Induced by Reactive Oxygen Species in Systemic Sclerosis Fibroblasts

• Published in: International journal of molecular sciences 2020-04, Vol.21 (9), p.3161
• Main Authors: Di Luigi, Luigi, Sgrò, Paolo, Duranti, Guglielmo, Sabatini, Stefania, Caporossi, Daniela, Del Galdo, Francesco, Dimauro, Ivan, Antinozzi, Cristina
• Format: Article
• Language: English
• Subjects: AKT protein; Cardiomyocytes; Cells, Cultured; Communication; Cytokines; Damage prevention; Fibroblasts; Fibroblasts - drug effects; Fibroblasts - metabolism; Gene expression; Gene Expression Regulation - drug effects; Humans; Hydrogen peroxide; Hydrogen Peroxide - metabolism; Hydrogen Peroxide - pharmacology; Inflammation; Interleukin 6; Interleukin 8; Interleukin-6 - genetics; Interleukin-6 - metabolism; Interleukin-8 - genetics; Interleukin-8 - metabolism; Neutrophils; NF-κB protein; Oxidative stress; Oxidative Stress - drug effects; Pathogenesis; PDE5 inhibitors; Phosphodiesterase; Phosphodiesterase 5 Inhibitors - pharmacology; Reactive oxygen species; Reactive Oxygen Species - metabolism; Risk analysis; Risk factors; Scleroderma; Scleroderma, Systemic - genetics; Scleroderma, Systemic - metabolism; Sildenafil; Sildenafil Citrate - pharmacology; Skin; Stat3 protein; Systemic sclerosis; Transcription, Genetic
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms21093161

Oxidative stress linked to vascular damage plays an important role in the pathogenesis of systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients with Raynaud's Phenomenon (RP) is a major risk factor for the development of SSc together with the presence of specific autoantiobodies. Here, we investigated the effects of the phosphodiesterase type 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating the proinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblasts isolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species (ROS) (100 µM H O ), in the presence or absence of sildenafil (1 µM). Treatment with sildenafil significantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to play a central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. This reduction was associated with suppression of STAT3-, ERK-, NF-κB-, and PKB/AKT-dependent pathways. Our findings support the notion that the employment of PDE5i in the management of RP may be explored for its efficacy in modulating the oxidative stress-induced proinflammatory activation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damage caused by SSc.