Pro-Resolution Potency of Resolvins D1, D2 and E1 on Neutrophil Migration and in Dermal Wound Healing

Abstract

An exuberant inflammatory response may exacerbate the primary tissue damage caused by injuries to the skin due to burns, surgery, excessive pressure, and other etiologies, thus increasing the time to heal. We hypothesized that application of factors that decrease inflammation would allow the skin to more quickly restore its barrier function, and promote the return to homeostasis. Resolvins are endogenous, pro-resolving lipid mediators derived from omega-3 fatty acids that serve to inhibit neutrophil migration and enhance macrophage phagocytosis, thus promoting the resolution of inflammation and the beginning of the proliferative phase of wound healing. Resolvins are derived either from docosahexaenoic (D-series) or eicosapentaenoic (E-series) acid. Herein, we compare the effects of resolvins D1 (RvD1), D2 (RvD2) and E1 (RvE1) on their abilities to inhibit neutrophil migration in vitro and to promote wound healing in vivo. In Transwell experiments, all resolvins inhibited neutrophil migration, with RvE1 being the most effective at a 2000nM concentration. In an in vivo murine excisional wound (1cm × 1cm) healing model, topically applied resolvins accelerated wound closure. RvE1-treated wounds healed by 19.4 ± 1.5 days post-wounding, which was significantly shorter than the RvD2-treated and RvD1-treated groups (p<0.05), which closed by an average of 22.8 ± 1.8 and 24.4 ± 2.2 days, respectively. Furthermore, all resolvin-treated groups healed faster than vehicle controls (p<0.05), which closed at 28.6 ± 1.5 days. There was a strong linear correlation (R2=0.9384) between each resolvin's potency in inhibiting neutrophil migration in vitro versus accelerating wound healing in vivo. Furthermore, upon histological analysis, the RvE1-treated group exhibited more mature collagen organization and reepithelialization.