M. AOKI2,3, T. Tsuge3, H. Aoki2,4, P. Mukhopadhyay2, H. Yamamoto5, N. M. Matsumoto3, E. Toyohara3, R. Ogawa3, K. Takabe1,2,6,7,8,9 1Roswell Park Cancer Institute,Division Of Breast Surgery, Department Of Surgical Oncology,Buffalo, NY, USA 2Virginia Commonwealth University,Division Of Surgical Oncology, Department Of Surgery,Richmond, VA, USA 3Nippon Medical School,Department Of Plastic, Reconstructive, And Aesthetic Surgery,Bunkyo, TOKYO, Japan 4Jikei University,Department Of Surgery,Minato, TOKYO, Japan 5Osaka University,Department Of Molecular Pathology,Osaka, OSAKA, Japan 6State University Of New York At Buffalo,Department Of Surgery,Buffalo, NY, USA 7Tokyo Medical University,Department Of Breast Surgery And Oncology,Shinjuku, Tokyo, Japan 8Yokohama City University,Department Of Surgery,Yokohama, KANAGAWA, Japan 9Niigata University Graduate School of Medical and Dental Sciences,Department Of Surgery,Niigata, NIIGATA, Japan
Introduction: Wound healing starts with the recruitment of inflammatory cells, which is followed by fibroblast activation and tissue construction. Deep dermal burn (DDB) can easily progress to a deeper injury due to infection through necrotic tissues and requires a long time to heal. A novel treatment that can enhance local immunity and promote epithelialization may achieve a breakthrough in burn management. S1P is a lipid mediator that promotes angiogenesis and cell proliferation, and is indispensable for local immunity. We investigated the roles of S1P in wound healing and its effects in DDB treatment.
Methods: A murine excisional wound splinting model was used. The mRNA expression of sphingosine kinase 1/2 (SphK1/2), and S1P receptor 1/2 (S1PR1/2) in the wound were measured. Rates of wound closure in SphK1-/- and S1PR2-/- were compared with wild type mice. The effects of nanoparticle-mediated topical SphK1 plasmid delivery were compared with control treatments. Rat DDBs were created by contact with 78°C water for 10 seconds. The effects of topical application with control or S1P ointment were analyzed.
Results: SphK1 was highly expressed in murine wounds and SphK1-/- mice exhibited delayed wound closure along with reduced angiogenesis and inflammatory cell recruitment. Nanoparticle-mediated topical SphK1 overexpression accelerated wound closure, which was associated with increased angiogenesis, inflammatory cell recruitment, and various wound-related factors. SphK1 overexpression also led to less scarring, and suggested the interaction between tumor growth factor (TGF) -β1 and S1P. Topical application of S1P accelerated rat DDB wound closure with increased angiogenesis and macrophage recruitment.
Conclusion: SphK1 plays an important role in strengthening immunity, and promoting rapid wound healing with less scarring. Topical application of S1P promotes DDB wound healing by recruitment of macrophages and enhanced angiogenesis. S1P can be a candidate for a novel treatment for burn wounds to reduce necrotic tissues, prevent infection, and promote epithelialization.