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.

Pseudomonas aeruginosa biofilm hampers murine central wound healing by suppression of vascular epithelial growth factor

“…In a recent clinical study, our group found a correlation between levels of lipopolysaccharide and VEGF in chronic wounds fluids . Tissue hypoxia strongly induces VEGF levels .…”

“…We previously reported reduced levels of S100A8/A9 in non‐healing human and in infected murine chronic wounds . The present study supports the suppressing effect of P. aeruginosa biofilm on host level of S100A8/A9, especially located towards the centre of the wounds at the earliest point of the evaluation stages (4 DPI).…”

“…We previously described a correlation between VEGF and levels of bacterial lipopolysaccharide in human wounds . Furthermore, we described a suppressive effect of biofilms on innate host defence protein S100A8/A9 in human and whole murine wounds .…”

Immune Modulating Topical S100A8/A9 Inhibits Growth of Pseudomonas aeruginosa and Mitigates Biofilm Infection in Chronic Wounds

“…S100A8/A9 has wide antifungal and antimicrobial potential [ 8 ]. We previously reported reduced S100A8/A9 levels in colonized human chronic wounds [ 9 , 10 ]. Since P. aeruginosa is able to degrade cytokines [ 11 ], S100A8/A9 may likewise be degraded in vivo in anatomically close proximity to the P. aeruginosa biofilm as part of the evasion of the immune system.…”

Animal models of chronic wound care: the application of biofilms in clinical research

“…27 If the fundamental disposing factor is not corrected, the colonization will proceed to the establishment of a permanent state of biofilm infection ultimately perturbing and impairing the host response. [28][29][30] Microbes gaining access to exposed subcutaneous fatty tissue will be able to cause local infection as the mature biofilm is resistant to host response and antimicrobial therapy. 29 Human comorbidity such as systemic disease with chronically elevated inflammatory markers, malnutrition, fluctuating glucose levels, or neuropathies is a conducive microenvironment for a biofilm establishment.…”