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S100A8/A9 deficiency in nonhealing venous leg ulcers uncovered by multiplexed antibody microarray profiling

Published on Aug 1, 2011in British Journal of Dermatology 6.13
· DOI :10.1111/j.1365-2133.2011.10384.x
Hannah Trøstrup3
Estimated H-index: 3
,
Rasmus Lundquist4
Estimated H-index: 4
+ 4 AuthorsMagnus S. Ågren30
Estimated H-index: 30
Abstract
Summary Background  Knowledge on the underlying mechanisms for nonhealing chronic wounds is fragmentary. Objectives  To increase our understanding of the pathogenesis, the relationship between healing ability and a large panel of proteins was studied using a specially designed wound-healing antibody-based microarray. Methods  Wound fluid from nondiabetic patients with nonhealing venous leg ulcers was compared with that from patients with healing open granulating acute wounds. The high-throughput method enabled simultaneous measurement of the relative levels of 48 different proteins representing major categories of wound-healing modulators. Results  Unexpectedly, several of the examined proteins, including various proinflammatory cytokines, proteinases and antiproteinases, were not significantly (P > 0·001) changed in chronic wound fluid. For example, levels of matrix metalloproteinase-9 and one of its substrates type IV collagen were similar in the two groups. The wound fluid samples displayed similar degrees of fragmentation of fibronectin by Western blot analysis and the total fibronectin levels were doubled (P < 0·001) in chronic compared with acute wounds. The increased fibronectin originated from α-smooth muscle actin-positive myofibroblasts and not from the circulation. S100A8/A9 was the sole protein that was reduced (P < 0·001) in wound fluid from venous ulcers [median 226 μg mL−1 (interquartile range 213–278)] compared with healing wounds [455 μg mL−1 (382–504)], probably reflecting a difference in inflammatory cell composition. Conclusion  The molecular anomalies in chronic wounds are more subtle than the current paradigm and neither excessive proteinase activity nor deficiencies of examined extracellular matrix proteins, growth factors or angiogenic/angiostatic factors appear to contribute significantly to the nonhealing state of venous leg ulcers.
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  • Citations (23)
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References48
Newest
Published on Sep 1, 2011in Acta Dermato-venereologica
Grönberg A1
Estimated H-index: 1
,
Zettergren L1
Estimated H-index: 1
,
Agren Ms1
Estimated H-index: 1
22 Citations Source Cite
Published on Apr 1, 2011in Journal of Investigative Dermatology 6.45
Yen Chen Liu1
Estimated H-index: 1
(University of California, Davis),
David J. Margolis77
Estimated H-index: 77
(University of Pennsylvania),
Roslyn Rivkah Isseroff40
Estimated H-index: 40
(University of California, Davis)
Chronic venous disease, a disorder involving venous return from the legs, is a growing epidemic in the developed world. Numerous studies have been conducted in the past two decades in an attempt to elucidate its underlying pathophysiology. Many theories have been proposed to address the profound inflammatory dysregulation, with the majority focusing on fibrin trap, inflammatory trap, cytokines, growth factors, and matrix metalloproteinases. Although many of these theories have obtained great mom...
31 Citations Source Cite
Published on Jan 21, 2011in FEBS Letters 3.00
Andreas Voss4
Estimated H-index: 4
(University of Münster),
Günther Bode7
Estimated H-index: 7
(University of Münster)
+ 5 AuthorsClaus Kerkhoff26
Estimated H-index: 26
(University of Münster)
S100A8/A9 promotes NADPH oxidase in HaCaT keratinocytes and subsequently increases NFκB activation, which plays important roles in the balance between epidermal growth and differentiation. S100A8/A9-positive HaCaT cells present with a significantly reduced rate of cell division and greater expression of two keratinocyte differentiation markers, involucrin and filaggrin, than control cells. S100A8/A9 mutants fail to enhance NFκB activation, TNFα-induced IL-8 gene expression and NFκB p65 phosphory...
26 Citations Source Cite
Published on Jan 1, 2011in BMJ clinical evidence
E. A. Nelson14
Estimated H-index: 14
,
Adderley U1
Estimated H-index: 1
Introduction Leg ulcers usually occur secondary to venous reflux or obstruction, but 20% of people with leg ulcers have arterial disease, with or without venous disorders. Between 1.5 and 3.0/1000 people have active leg ulcers. Prevalence increases with age to about 20/1000 in people aged over 80 years.
105 Citations
Published on Jan 1, 2011in Plastic and Reconstructive Surgery 3.62
Joseph D. Raffetto28
Estimated H-index: 28
,
William A. Marston36
Estimated H-index: 36
Summary: The pathophysiology of venous dermal abnormality in chronic venous ulcers is reflective of a complex interplay that involves sustained venous hypertension, inflammation, changes in the microcirculation, cytokine and matrix metalloproteinase activation, and altered cellular function. Red blood cells and macromolecules extravasate into the interstitium and activate endothelial cells. Endothelial expression of specific adhesion molecules recruits leukocytes and causes diapedesis of these c...
17 Citations Source Cite
Published on Oct 1, 2010in Journal of Investigative Dermatology 6.45
Arby Abtin6
Estimated H-index: 6
(Medical University of Vienna),
Leopold Eckhart29
Estimated H-index: 29
(Medical University of Vienna)
+ 3 AuthorsErwin Tschachler60
Estimated H-index: 60
(Medical University of Vienna)
Antimicrobial peptides (AMPs) have a central role in the innate immune system of the skin. Epidermal keratinocytes (KCs) express numerous such peptides either constitutively or in response to exposure to microbial compounds. Here, we investigated the regulation of S100A8 (calgranulin A) and S100A9 (calgranulin B), which form an antimicrobial heterodimeric complex also known as calprotectin, in KCs. Culture supernatants of Gram-negative bacteria, but not of Gram-positive bacteria nor of the yeast...
44 Citations Source Cite
Published on Sep 3, 2010in Journal of Proteome Research 3.95
Sabine A. Eming36
Estimated H-index: 36
,
Manuel Koch42
Estimated H-index: 42
+ 6 AuthorsJay W. Fox52
Estimated H-index: 52
Chronic wounds associated with vascular disease, diabetes mellitus, or aging are leading causes of morbidity in western countries and represent an unresolved clinical problem. The development of innovative strategies to promote tissue repair is therefore an important task that requires a more thorough analysis of the underlying molecular pathophysiology. We propose that the understanding of the complex biological events that control tissue repair or its failure largely benefits from a broad anal...
114 Citations Source Cite
Published on Aug 1, 2010in Archives of Dermatological Research 2.15
Cornelia Wiegand18
Estimated H-index: 18
,
Ute Schönfelder3
Estimated H-index: 3
+ 3 AuthorsUta-Christina Hipler28
Estimated H-index: 28
Physiological wound repair is a highly regulated, complex process, which leads to formation of new tissue after injury. However, the healing process is not perfect and healing impairments can occur. Delayed healing and formation of chronic wounds has been linked to the excessive production of proteolytic enzymes leading to reduced amounts of growth factors and successive destruction of the extracellular matrix. It has been implied that there is an alteration in the normal control mechanisms regu...
60 Citations Source Cite
Published on May 1, 2010in Annals of Surgery 9.20
Brian B. Haab34
Estimated H-index: 34
(Van Andel Institute),
Andrew Porter2
Estimated H-index: 2
(Van Andel Institute)
+ 7 AuthorsDiane M. Simeone53
Estimated H-index: 53
BACKGROUND AND AIMS Cystic lesions of the pancreas are increasingly being recognized due to the widespread use of high resolution abdominal imaging. Since certain cyst types are precursors to invasive cancer, this situation presents an opportunity to intervene prior to malignant progression. Effective implementation of that strategy has been hampered by difficulties in clearly distinguishing cystic lesions with no malignant potential from those with malignant potential. Here we explored whether ...
71 Citations Source Cite
Published on Apr 1, 2010in Journal of Investigative Dermatology 6.45
K. Markus Roupé4
Estimated H-index: 4
(Lund University),
Mads Nybo23
Estimated H-index: 23
(Odense University Hospital)
+ 3 AuthorsOle E. Sørensen40
Estimated H-index: 40
(Lund University)
We examined the importance of injury for the epidermal innate immune response in human skin wounds. We found that injury, independent of infiltrating inflammatory cells, generated prominent chemotactic activity toward neutrophils in injured skin because of IL-8 production. Furthermore, injury was a major inducer of the expression of antimicrobial (poly)peptides (AMPs) in skin wounds. In human skin, these injury-induced innate immune responses were mediated by activation of the epidermal growth f...
85 Citations Source Cite
Cited By23
Newest
Chih-Ru Lin1
Estimated H-index: 1
,
Karim Bahmed5
Estimated H-index: 5
+ 6 AuthorsBeata Kosmider14
Estimated H-index: 14
(Temple University)
Pulmonary emphysema is characterized by alveolar wall destruction, and cigarette smoking is the main risk factor in this disease development. S100A8 is a member of the S100 protein family, with an oxidative stress–related and antiinflammatory role. The mechanisms of human alveolar type II (ATII) cell injury contributing to emphysema pathophysiology are not completely understood. We wanted to determine whether S100A8 can protect ATII cells against injury induced by cigarette smoke and this diseas...
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Published on Dec 1, 2018in Scientific Reports 4.12
Abhijit Basu4
Estimated H-index: 4
(University of Ulm),
Saira Munir1
Estimated H-index: 1
(University of Ulm)
+ 8 AuthorsFlorian Gebhard40
Estimated H-index: 40
(University of Ulm)
We here investigated whether the unique capacity of mesenchymal stem cells (MSCs) to re-establish tissue homeostasis depends on their potential to sense danger associated molecular pattern (DAMP) and to mount an adaptive response in the interest of tissue repair. Unexpectedly, after injection of MSCs which had been pretreated with the calcium-binding DAMP protein S100A8/A9 into murine full-thickness wounds, we observed a significant acceleration of healing even exceeding that of non-treated MSCs...
3 Citations Source Cite
Published on Nov 2, 2018in Journal of Wound Care 1.67
Hannah Trøstrup3
Estimated H-index: 3
(University of Copenhagen),
Per Holstein8
Estimated H-index: 8
(University of Copenhagen)
+ 2 AuthorsMagnus S. Ågren14
Estimated H-index: 14
(University of Copenhagen)
Objective: To compare matrix metalloproteinase (MMP)-9 and the antiproteinase tissue inhibitor of metalloproteinases (TIMP)-1 in wound fluids and sera from patients with chronic non-healing or acute healing wounds. In addition, the functional consequences on MMP-9 activity and general gelatinase activity were assessed. Method: In this observational study, samples were collected from patients with venous leg ulcers (VLUs), patients with type 2 diabetes with neuropathic foot ulcers (DFUs), and fro...
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Published on Feb 1, 2018in International Wound Journal 2.38
Hannah Trøstrup6
Estimated H-index: 6
(Copenhagen University Hospital),
Christian Johann Lerche3
Estimated H-index: 3
(Copenhagen University Hospital)
+ 5 AuthorsClaus Moser34
Estimated H-index: 34
(Copenhagen University Hospital)
1 Citations Source Cite
Published on Oct 30, 2017in Cochrane Database of Systematic Reviews 6.75
Maggie J Westby4
Estimated H-index: 4
,
Jo C Dumville36
Estimated H-index: 36
+ 4 AuthorsRichard D Riley37
Estimated H-index: 37
(Keele University)
This is a protocol for a Cochrane Review (Prognosis). The objectives are as follows: To determine whether protease activity is an independent prognostic factor for the healing of venous leg ulcers.
1 Citations Source Cite
Published on Jun 26, 2017in International Journal of Molecular Sciences 3.69
Hannah Trøstrup6
Estimated H-index: 6
,
Christian Johann Lerche3
Estimated H-index: 3
+ 3 AuthorsClaus Moser34
Estimated H-index: 34
Pseudomonas aeruginosa biofilm maintains and perturbs local host defense, hindering timely wound healing. Previously, we showed that P. aeruginosa suppressed S100A8/A9 of the murine innate host defense. We assessed the potential antimicrobial effect of S100A8/A9 on biofilm-infected wounds in a murine model and P. aeruginosa growth in vitro. Seventy-six mice, inflicted with a full-thickness burn wound were challenged subcutaneously (s.c.) by 106 colony-forming units (CFUs) of P. aeruginosa biofil...
1 Citations Source Cite
Published on Jun 22, 2017in Fems Immunology and Medical Microbiology 2.34
Hannah Trøstrup6
Estimated H-index: 6
(Copenhagen University Hospital),
Christian Johann Lerche3
Estimated H-index: 3
(Copenhagen University Hospital)
+ 5 AuthorsClaus Moser34
Estimated H-index: 34
(Copenhagen University Hospital)
1 Citations Source Cite
Published on Apr 1, 2017in Apmis 2.03
Claus Moser34
Estimated H-index: 34
(Copenhagen University Hospital),
Hannah Trøstrup Pedersen1
Estimated H-index: 1
(Copenhagen University Hospital)
+ 5 AuthorsPeter Østrup Jensen43
Estimated H-index: 43
(University of Copenhagen)
13 Citations Source Cite
Published on Sep 1, 2016in Wound Repair and Regeneration 2.95
Domenico Taverna13
Estimated H-index: 13
(Vanderbilt University),
Alonda C. Pollins14
Estimated H-index: 14
(Vanderbilt University)
+ 2 AuthorsLillian B. Nanney53
Estimated H-index: 53
(Vanderbilt University)
7 Citations Source Cite
Published on Jul 1, 2016in Archives of Dermatological Research 2.15
Hannah Trøstrup3
Estimated H-index: 3
(University of Copenhagen),
Per Holstein8
Estimated H-index: 8
(University of Copenhagen)
+ 5 AuthorsMagnus S. Ågren14
Estimated H-index: 14
(University of Copenhagen)
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...
6 Citations Source Cite