Dasatinib Ointment Promotes Healing of Murine Excisional Skin Wound

Dasatinib, a tyrosinekinase inhibitor, has been shown to produceanti-inflammatory activity and impair vascular integrity in vivo,including during skin wound healing, potentially promoting the repairprocess. Given that dasatinib is a lipophilic small molecule capableof penetrating skin, topical dasatinib might provide benefits in woundhealing. In the present study, we investigated the impact of dasatinibointments in skin wound healing in mice. A full thickness excisionalskin wound (4 mm diameter) was generated on the shaved dorsum of eight-week-oldC57BL/6 mice. Dasatinib ointment (0.1 or 0.2% w/w) or ointment basewas applied twice daily (every 12 h) for 10 days. Elizabethan collarswere used to prevent animal licking. The wound size was monitoreddaily for 14 days. The results showed that dasatinib ointments, particularly0.1% dasatinib, promoted a 16-23% reduction in wound size (p < 0.05) during day 2 to day 6 postinjury compared tocontrols. Immunohistochemistry analyses demonstrated a reduction inwound neutrophils (38% reduction, p = 0.04), macrophages(47% reduction, p = 0.005), and tumor necrosis factor-alpha levels (73% reduction, p < 0.01), together withan induction of vascular leakage-mediated fibrin(ogen) accumulation(2.5-fold increase, p < 0.01) in the wound duringday 3 postinjury (an early phase of repair) in 0.1% dasatinib-treatedmice relative to control mice. The anti-inflammatory and vascularhyperpermeability activities of dasatinib were associated with anenhanced healing process, including increased keratinocyte proliferation(1.8-fold increase in Ki67(+) cells, p <0.05) and augmented angiogenesis (1.7-fold increase in CD31(+) area, p < 0.05), compared to the ointment base-treatedgroup. Following treatment with 0.2% dasatinib ointment, minor woundbleeding and scab reformation were observed during the late phase,which contributed to delayed healing. In conclusion, our data suggestthat dasatinib ointment, mainly at 0.1%, promotes the repair processby reducing inflammation and producing a local and temporal vascularleakage, leading to an increase in fibrin(ogen) deposition, re-epithelialization,and angiogenesis. Therefore, topical dasatinib might be a potentialnovel candidate to facilitate skin wound healing.