Sildenafil reduces expression and release of IL-6 and IL-8 induced by reactive oxygen species in systemic sclerosis fibroblasts

Oxidative stress linked to vascular damage plays an important role in the pathogenesisof systemic sclerosis (SSc). Indeed, vascular damage at nailfold capillaroscopy in patients withRaynaud’s Phenomenon (RP) is a major risk factor for the development of SSc together with thepresence of specific autoantiobodies. Here, we investigated the e ects of the phosphodiesterasetype 5 inhibitor (PDE5i) sildenafil, currently used in the management of RP, in modulating theproinflammatory response of dermal fibroblasts to oxidative stress in vitro. Human fibroblastsisolated from SSc patients and healthy controls were exposed to exogenous reactive oxygen species(ROS) (100 M H2O2), in the presence or absence of sildenafil (1 M). Treatment with sildenafilsignificantly reduced dermal fibroblast gene expression and cellular release of IL-6, known to playa central role in the pathogenesis of tissue damage in SSc and IL-8, directly induced by ROS. Thisreduction was associated with suppression of STAT3-, ERK-, NF- B-, and PKB/AKT-dependentpathways. Our findings support the notion that the employment of PDE5i in the management ofRP may be explored for its e cacy in modulating the oxidative stress-induced proinflammatoryactivation of dermal fibroblasts in vivo and may ultimately aid in the prevention of tissue damagecaused by SSc.