S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus

Hannah Trøstrup; Per Holstein; Lars Christophersen; Bo Jørgensen; Tonny Karlsmark; Niels Høiby; Claus Moser; Magnus S. Ågren

doi:10.1007/s00403-016-1646-7

S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus

Hannah Trøstrup, Per Holstein, Lars Christophersen, Bo Jørgensen, Tonny Karlsmark, Niels Høiby, Claus Moser, Magnus S. Ågren^*

^*Corresponding author af dette arbejde

Institut for Klinisk Medicin

11 Citationer (Scopus)

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.

Originalsprog	Engelsk
Tidsskrift	Archives of Dermatological Research
Vol/bind	308
Udgave nummer	5
Sider (fra-til)	347-355
Antal sider	9
ISSN	0340-3696
DOI	https://doi.org/10.1007/s00403-016-1646-7
Status	Udgivet - 1 jul. 2016

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10.1007/s00403-016-1646-7

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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{\textquoteright} sera. Low S100A8/A9 levels may contribute to poor wound healing in colonized chronic wounds with striking difference between DFUs and VLUs.",

keywords = "Calprotectin, Chronic wound, Cytokine, Endotoxin, Innate immunity",

author = "Hannah Tr{\o}strup and Per Holstein and Lars Christophersen and Bo J{\o}rgensen and Tonny Karlsmark and Niels H{\o}iby and Claus Moser and {\AA}gren, {Magnus S.}",

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T1 - S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus

AU - Trøstrup, Hannah

AU - Holstein, Per

AU - Christophersen, Lars

AU - Jørgensen, Bo

AU - Karlsmark, Tonny

AU - Høiby, Niels

AU - Moser, Claus

AU - Ågren, Magnus S.

PY - 2016/7/1

Y1 - 2016/7/1

N2 - 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.

AB - 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.

KW - Calprotectin

KW - Chronic wound

KW - Cytokine

KW - Endotoxin

KW - Innate immunity

U2 - 10.1007/s00403-016-1646-7

DO - 10.1007/s00403-016-1646-7

M3 - Journal article

C2 - 27084691

AN - SCOPUS:84963781690

SN - 0340-3696

VL - 308

SP - 347

EP - 355

JO - Archiv für Dermatologische Forschung

JF - Archiv für Dermatologische Forschung

IS - 5

ER -

S100A8/A9 is an important host defence mediator in neuropathic foot ulcers in patients with type 2 diabetes mellitus

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