A synthetic leukotriene B4 receptor type 2 agonist accelerates the cutaneous wound healing process in diabetic rats by indirect stimulation of fibroblasts and direct stimulation of keratinocytes

Aims: The synthetic leukotriene B-4 receptor type 2 (BLT2) agonist CAY10583 (CAY) accelerates wound healing in diabetic mice by promoting keratinocyte migration. However, its effects on fibroblast activity and granulation are unknown. We investigated the mechanisms by which CAY promotes wound healing. Methods: CAY was applied to wounds on streptozotocin-induced diabetic rats, and wound closure, granulation thickness, and epithelialization gaps were analyzed. BLT2 expression was examined by RT-PCR. Migration and proliferation were studied by scratch assays and MTS assays. Keratinocyte supernatants with CAY were applied to fibroblasts, and cytokines were measured by enzyme-linked immunosorbent assays. Results: CAY significantly accelerated wound healing in diabetic rats (CAY, 78.05 +/- 12.22% vs. control, 59.84 +/- 11.09%; p = 0.0222), with increased re-epithelialization and granulation compared to controls. BLT2 was expressed in keratinocytes, but not in fibroblasts. Keratinocyte treatment with the CAY supernatant enhanced fibroblast proliferation and migration (fibroblast scratch closure: CAY, 75.95 +/- 4.09% vs. control, 49.69 +/- 4.49%; p < 0.0001). CAY-treated keratinocytes exhibited increased TGF-beta 1 and bFGF expression. Conclusions: CAY directly promotes keratinocyte migration and indirectly enhances fibroblast proliferation by increasing keratinocyte production of TGF-beta 1 and bFGF, accelerating wound closure. CAY is a promising pharmaceutical agent for diabetic wounds. (C) 2017 The Authors. Published by Elsevier Inc.