Anti-scarring activity of a Gardos channel inhibitor in severe burn injuries

A pathophysiological hallmark of hypertrophic scarring is the overactivation of fibroblasts, which results in their proliferation along with overproduction of the extracellular matrix. The Gardos channel (KCa3.1) is reported to mediate fibroblast activation in multiple clinical conditions; however, its role in the post-burn hypertrophic skin scar formation is unknown. This study aimed to investigate the role of KCa3.1 and anti-fibrotic potential of senicapoc, a KCa3.1 inhibitor, in post-burn hypertrophic scar formation. Cell proliferation and expression of hypertrophic markers were investigated in fibroblasts obtained directly from patients within 1–2 weeks of suffering third-degree burns who subsequently developed post-burn hypertrophic scars. The anti-fibrotic effects of senicapoc via KCa3.1 inhibition were assessed using in vitro fibroblasts and in vivo burn models in mice. Increased cell proliferation and expression of hypertrophic markers were identified in burn-wound fibroblasts obtained from patients. The targeted inhibition of KCa3.1 by senicapoc significantly reduced cell proliferation along with the expression of hypertrophic markers in burn-wound fibroblasts from patients. In addition, the anti-scarring effect following senicapoc administration was confirmed using murine burn models in terms of molecular, histological, and visual aspects. This study demonstrated altered cellular and molecular responses of skin fibroblasts from patients after third-degree burns. In addition, this study confirmed an anti-fibrotic effect of KCa3.1 inhibition by senicapoc in both in vitro within burn fibroblasts and in vivo within murine burn models. These results suggest that selective inhibition of KCa3.1 by senicapoc has therapeutic potential to prevent hypertrophic scar formation following burns.