title: S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus.
abstract: Chronic wounds and in particular diabetic foot ulcers (DFUs) are a growing clinical challenge, but the underlying molecular pathophysiological mechanisms are unclear. Recently, we reported reduced levels of the immunomodulating and antimicrobial S100A8/A9 in non-healing venous leg ulcers (VLUs), while another study found increased S100A8/A9 in DFUs. To clarify these apparently contradictory findings, we compared S100A8/A9 as well as an inducer, lipopolysaccharide (LPS) and selected innate immune response mediators in wound fluids from non-healing DFUs and VLUs with healing wounds. Wound fluids were collected from neuropathic DFUs (n = 6) and VLUs (n = 9) of median 2-year duration, and split-thickness skin graft donor site wounds (n = 10) by standardized method. None of the patients had ischaemic extremities or clinically infected wounds. LPS was determined by limulus amoebocyte lysate test, and S100A8/A9, granulocyte colony-stimulating factor (G-CSF), interleukin (IL)-10 and vascular endothelial growth factor (VEGF) by immunospecific quantitative assays. LPS levels were median 8.7 (interquartile range 5.4-21.2) ng/ml in DFUs compared with 121 (22-2000) ng/ml in VLUs. S100A8/A9 was higher (p = 0.020) in DFUs [718 (634-811) µg/ml] than in VLUs [303 (252-533) µg/ml]. Neither G-CSF nor IL-10 wound fluid levels differed significantly between the chronic wound groups. VEGF levels correlated with LPS (r = 0.758, p = 0.011, n = 10) and were higher (p = 0.024) in VLU wound fluids. LPS (p < 0.0001), S100A8/A9 (p = 0.005), G-CSF (p = 0.003), IL-10 (p = 0.003) and VEGF (p = 0.005) were increased in chronic wound fluids combined compared with the sterile donor site wound fluids. The protein alterations in the wounds were not reflected in the patients' sera. Low S100A8/A9 levels may contribute to poor wound healing in colonized chronic wounds with striking difference between DFUs and VLUs.
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Hannah
authors.initials: H
authors.lastname: Trøstrup
authors.affiliation: Copenhagen Wound Healing Center, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Per
authors.initials: P
authors.lastname: Holstein
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Lars
authors.initials: L
authors.lastname: Christophersen
authors.affiliation: Copenhagen Wound Healing Center, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Bo
authors.initials: B
authors.lastname: Jørgensen
authors.affiliation: Copenhagen Wound Healing Center, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Tonny
authors.initials: T
authors.lastname: Karlsmark
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.|Institute for International Health, Immunology and Microbiology, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Niels
authors.initials: N
authors.lastname: Høiby
authors.affiliation: Department of Clinical Microbiology, Rigshospitalet, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Claus
authors.initials: C
authors.lastname: Moser
authors.affiliation: Copenhagen Wound Healing Center, University of Copenhagen, Copenhagen, Denmark. magnus.agren@mail.dk.|Digestive Disease Center, Bispebjerg Hospital, University of Copenhagen, Copenhagen, Denmark. magnus.agren@mail.dk.|Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. magnus.agren@mail.dk.
authors.forename: Magnus S
authors.initials: MS
authors.lastname: Ågren
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002908:Chronic Disease; D003924:Diabetes Mellitus, Type 2 / Q000150:complications*; D017719:Diabetic Foot / Q000276:immunology* / Q000378:metabolism; D003929:Diabetic Neuropathies / Q000276:immunology* / Q000378:metabolism; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate; D016753:Interleukin-10 / Q000378:metabolism; D039841:Leukocyte L1 Antigen Complex / Q000276:immunology / Q000378:metabolism*; D008033:Limulus Test; D008070:Lipopolysaccharides / Q000378:metabolism*; D008297:Male; D008875:Middle Aged; D014647:Varicose Ulcer / Q000276:immunology* / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D014945:Wound Healing / Q000276:immunology*
chemical_list: C508609:IL10 protein, human; D039841:Leukocyte L1 Antigen Complex; D008070:Lipopolysaccharides; D042461:Vascular Endothelial Growth Factor A; D016753:Interleukin-10; D016179:Granulocyte Colony-Stimulating Factor
keywords: Calprotectin; Chronic wound; Cytokine; Endotoxin; Innate immunity