title: A synthetic leukotriene B4receptor type 2 agonist accelerates the cutaneous wound healing process in diabetic rats by indirect stimulation of fibroblasts and direct stimulation of keratinocytes.
abstract: The synthetic leukotriene B4receptor 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.
  
  
  
  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.
  
  
  
  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-β1 and bFGF expression.
  
  
  
  CAY directly promotes keratinocyte migration and indirectly enhances fibroblast proliferation by increasing keratinocyte production of TGF-β1 and bFGF, accelerating wound closure. CAY is a promising pharmaceutical agent for diabetic wounds.
authors.affiliation: Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China; Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address: donieluo@hotmail.com.
authors.forename: Lin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address: rtanaka@juntendo.ac.jp.
authors.forename: Rica
authors.initials: R
authors.lastname: Tanaka
authors.affiliation: Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address: sonic0311shige@yahoo.co.jp.
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Kanazawa
authors.affiliation: Department of Plastic and Reconstructive Surgery, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China. Electronic address: doctorlufeng@hotmail.com.
authors.forename: Feng
authors.initials: F
authors.lastname: Lu
authors.affiliation: Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address: ayhayasi@juntendo.ac.jp.
authors.forename: Ayato
authors.initials: A
authors.lastname: Hayashi
authors.affiliation: Department of Biochemistry, Juntendo University, 2-1-1 Hongo Bunkyo-ku, Tokyo 113-8421, Japan. Electronic address: yokomizo-tky@umin.ac.jp.
authors.forename: Takehiko
authors.initials: T
authors.lastname: Yokomizo
authors.affiliation: Department of Plastic and Reconstructive Surgery, Juntendo University, Tokyo 113-8421, Japan. Electronic address: hmizuno@juntendo.ac.jp.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuno
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000473:pathology* / Q000503:physiopathology; D005347:Fibroblasts / Q000187:drug effects* / Q000502:physiology; D015603:Keratinocytes / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D051381:Rats; D011917:Rats, Inbred Lew; D018102:Receptors, Leukotriene B4 / Q000819:agonists*; D012867:Skin / Q000166:cytology / Q000187:drug effects*; D013311:Streptozocin; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000975:Antioxidants; D018102:Receptors, Leukotriene B4; D013311:Streptozocin
keywords: Cay; Diabetes; Fibroblast; Keratinocyte; Leukotriene B(4) receptor type 2; Wound healing