title: Substance P promotes wound healing in diabetes by modulating inflammation and macrophage phenotype.
abstract: Diabetic foot ulceration is a major complication of diabetes. Substance P (SP) is involved in wound healing, but its effect in diabetic skin wounds is unclear. We examined the effect of exogenous SP delivery on diabetic mouse and rabbit wounds. We also studied the impact of deficiency in SP or its receptor, neurokinin-1 receptor, on wound healing in mouse models. SP treatment improved wound healing in mice and rabbits, whereas the absence of SP or its receptor impaired wound progression in mice. Moreover, SP bioavailability in diabetic skin was reduced as SP gene expression was decreased, whereas the gene expression and protein levels of the enzyme that degrades SP, neutral endopeptidase, were increased. Diabetes and SP deficiency were associated with absence of an acute inflammatory response important for wound healing progression and instead revealed a persistent inflammation throughout the healing process. SP treatment induced an acute inflammatory response, which enabled the progression to the proliferative phase and modulated macrophage activation toward the M2 phenotype that promotes wound healing. In conclusion, SP treatment reverses the chronic proinflammatory state in diabetic skin and promotes healing of diabetic wounds.
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Ermelindo C
authors: EC
authors: Leal
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Eugénia
authors: E
authors: Carvalho
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; Center for Neuroscience and Cell Biology, University of Coimbra, Coimbra, Portugal.
authors: Ana
authors: A
authors: Tellechea
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Antonios
authors: A
authors: Kafanas
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Francesco
authors: F
authors: Tecilazich
authors: Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; Department of Anatomy, Royal College of Surgeon's in Ireland, Dublin, Ireland.
authors: Cathal
authors: C
authors: Kearney
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Sarada
authors: S
authors: Kuchibhotla
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Michael E
authors: ME
authors: Auster
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Efi
authors: E
authors: Kokkotou
authors: Harvard School of Engineering and Applied Sciences, Harvard University, Cambridge, Massachusetts; Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, Massachusetts.
authors: David J
authors: DJ
authors: Mooney
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Frank W
authors: FW
authors: LoGerfo
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts.
authors: Leena
authors: L
authors: Pradhan-Nabzdyk
authors: Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts. Electronic address: aveves@bidmc.harvard.edu.
authors: Aristidis
authors: A
authors: Veves
mesh_terms: D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D003929:Diabetic Neuropathies / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007249:Inflammation / Q000378:metabolism* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D011817:Rabbits; D018040:Receptors, Neurokinin-1 / Q000235:genetics / Q000378:metabolism; D012867:Skin / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D013373:Substance P / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D014945:Wound Healing / Q000187:drug effects* / Q000502:physiology
chemical_list: D018040:Receptors, Neurokinin-1; D013373:Substance P