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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
H. Trøstrup1
Estimated H-index: 1
,
R. Lundquist1
Estimated H-index: 1
+ 4 AuthorsMagnus S. Ågren12
Estimated H-index: 12
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.
  • References (48)
  • Cited By (23)
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References48
Published on Mar 1, 2010in Molecular Medicine 3.34
Irena Pastar11
Estimated H-index: 11
(University of Miami),
Olivera Stojadinovic28
Estimated H-index: 28
(University of Miami)
+ 6 AuthorsMarjana Tomic-Canic38
Estimated H-index: 38
(University of Miami)
Abstract Transforming growth factor beta (TGFbeta) is important in inflammation, angiogenesis, reepithelialization and connective tissue regeneration during wound healing. We analyzed components of TGFbeta signaling pathway in biopsies from 10 patients with nonhealing venous ulcers (VUs). Using comparative genomics of transcriptional profiles of VUs and TGFbeta-treated keratinocytes, we found deregulation of TGFbeta target genes in VUs. Using quantitative polymerase chain reaction (qPCR) and imm...
69 Citations Source Cite
Published on Nov 1, 1992in American Journal of Pathology 4.07
Sarah E. Herrick27
Estimated H-index: 27
,
P. Sloan1
Estimated H-index: 1
+ 3 AuthorsMark W. J. Ferguson57
Estimated H-index: 57
As part of a major clinical trial, sequential biopsies were taken from the margins of venous leg ulcers during their healing. The changing patterns of tissue architecture and extracellular matrix synthesis during healing were documented histologically and immunocytochemically. Initial biopsies were similar in appearance: prominent fibrin cuffs, variable inflammation, hemosiderin, and red blood cell extravasation. So called "fibrin cuffs" were highly organized structures composed of laminin, fibr...
210 Citations
Published on Sep 1, 1997in Laboratory Investigation 4.26
Sarah E. Herrick27
Estimated H-index: 27
,
Gillian S. Ashcroft38
Estimated H-index: 38
+ 3 AuthorsMark W. J. Ferguson57
Estimated H-index: 57
Chronic wound healing states are often associated with aging, and despite the increased number of aged patients with nonhealing wounds, controversy still exists concerning the effects of age on wound repair. Our previous work showed that in both venous ulcers in humans and acute wounds in aged animals, fibronectin, an early component in granulation tissue, is deficient compared to normal skin and acute wounds in healthy young animals, respectively. In the present study, we have determined the pr...
109 Citations
Published on Oct 1, 2000in Nature Medicine 32.62
Gillian S. Ashcroft38
Estimated H-index: 38
(National Institutes of Health),
Kejian Lei4
Estimated H-index: 4
(National Institutes of Health)
+ 7 AuthorsSharon M. Wahl70
Estimated H-index: 70
(National Institutes of Health)
Secretory leukocyte protease inhibitor mediates non-redundant functions necessary for normal wound healing
313 Citations Source Cite
Published on Mar 30, 2004in Genome Biology 13.21
Heping Zhou4
Estimated H-index: 4
(Van Andel Institute),
Kerri Bouwman2
Estimated H-index: 2
(Van Andel Institute)
+ 6 AuthorsBrian B. Haab32
Estimated H-index: 32
(Van Andel Institute)
The ability to conveniently and rapidly profile a diverse set of proteins has valuable applications. In a step toward further enabling such a capability, we developed the use of rolling-circle amplification (RCA) to measure the relative levels of proteins from two serum samples, labeled with biotin and digoxigenin, respectively, that have been captured on antibody microarrays. Two-color RCA produced fluorescence up to 30-fold higher than direct-labeling and indirect-detection methods using antib...
133 Citations Source Cite
Published on Sep 1, 2006in Wound Repair and Regeneration 2.95
Magnus S. Ågren22
Estimated H-index: 22
(Copenhagen University Hospital),
Ulla Ostenfeld1
Estimated H-index: 1
(Copenhagen University Hospital)
+ 7 AuthorsLars N. Jorgensen2
Estimated H-index: 2
(Copenhagen University Hospital)
The purpose of this randomized, double-blind, placebo-controlled multicenter trial was to compare topical zinc oxide with placebo mesh on secondary healing pilonidal wounds. Sixty-four (53 men) consecutive patients, aged 17-60 years, were centrally randomized to either treatment with 3% zinc oxide (n=33) or placebo (n=31) by concealed allocation. Patients were followed with strict recording of beneficial and harmful effects including masked assessment of time to complete wound closure. Analysis ...
43 Citations Source Cite
Published on Jan 1, 2008in Wound Repair and Regeneration 2.95
Matthew Cardinal7
Estimated H-index: 7
,
David E. Eisenbud5
Estimated H-index: 5
+ 1 AuthorsKeith Gordon Harding48
Estimated H-index: 48
(Cardiff University)
This study was undertaken to determine if healing rates are reliable early predictors of ultimate complete wound closure in venous leg ulcers and diabetic foot wounds. We conducted a retrospective analysis of 306 venous leg ulcers and 241 diabetic foot ulcers enrolled in two large controlled, prospective, randomized pivotal trials to compare topical wound treatments, to determine whether certain early markers of healing could be correlated with later total wound closure. Two-sided tests at 95% c...
84 Citations Source Cite
Published on Jul 1, 1998in Plastic and Reconstructive Surgery 3.62
David P. Berry1
Estimated H-index: 1
,
Keith G. Harding1
Estimated H-index: 1
+ 2 AuthorsPaul H. Ehrlich1
Estimated H-index: 1
The closure of ungrafted sacrococcygeal pilonidal sinus excisional wounds was studied in 15 patients. Wound punch biopsies were taken on a regular basis, and histologic sections were made. To document changes, computer-assisted morphometric image analysis was employed. Initial average wound depth was 37.8 ± 4.6 mm, and complete closure (0 wound depth) was reached by 68 days. Wound contraction contributed 88 percent to wound closure, whereas the deposition of scar only contributed 12 percent. Max...
131 Citations Source Cite
Published on Jan 1, 1991in The Journal of Infectious Diseases 5.19
Peter G. Sohnle28
Estimated H-index: 28
,
Cathleen Collins-Lech12
Estimated H-index: 12
,
John H. Wiessner21
Estimated H-index: 21
Studies of experimental infections in animals indicate that phagocytic cells may sometimes control infective foci without actually ingesting or contacting the invading microorganisms. In the present study, an effective inhibitor of Candida albicans growth, previously detected in neutrophil cytoplasm and found to be released only after lysis of the cells, was identified as an abundant calcium-binding protein originally described in neutrophils as the L1 myelomonocytic antigen or the cystic fibros...
101 Citations Source Cite
Published on Feb 1, 1995in Journal of Investigative Dermatology 6.45
Elizabeth C. Bullen8
Estimated H-index: 8
(University of Oklahoma Health Sciences Center),
Michael T. Longaker95
Estimated H-index: 95
(New York University)
+ 4 AuthorsEric W. Howard22
Estimated H-index: 22
(University of Oklahoma Health Sciences Center)
The balance between matrix deposition and tissue turnover is fundamental in wound healing. It is likely that the balance between proteolytic enzymes and their inhibitors contributes to this balance. Matrix metalloproteinases are clearly important in tissue turnover, but their roles in wound healing are poorly understood, To investigate this, fluid from healing wounds resulting from mastectomies was collected from 1 h to 10 d post-surgery, and was analyzed for tissue inhibitor of metalloproteinas...
222 Citations Source Cite
Cited By23
Published on Sep 24, 2013in Current protocols in protein science
Brian B. Haab32
Estimated H-index: 32
(Van Andel Institute),
Katie Partyka8
Estimated H-index: 8
(Van Andel Institute),
Zheng Cao5
Estimated H-index: 5
(Van Andel Institute)
Antibody arrays provide a valuable method for obtaining multiple protein measurements from small volumes of biological samples. Antibody arrays can be designed to target not only core protein abundances (relative or absolute abundances, depending on the availability of standards for calibration), but also posttranslational modifications, provided antibodies or other affinity reagents are available to detect them. Glycosylation is a common modification that has important and diverse functions in ...
5 Citations Source Cite
Published on May 1, 2013in Wound Repair and Regeneration 2.95
Jodi C. McDaniel6
Estimated H-index: 6
(Ohio State University),
Sashwati Roy62
Estimated H-index: 62
(Ohio State University),
Traci A. Wilgus22
Estimated H-index: 22
(Ohio State University)
Chronic venous leg ulcers (CVLUs) affect approximately 600,000 people annually in the United States and accrue yearly treatment costs of US$2.5–5 billion. As the population ages, demands on health care resources for CVLU treatments are predicted to drastically increase because the incidence of CVLUs is highest in those ≥65 years of age. Furthermore, regardless of current standards of care, healing complications and high recurrence rates prevail. Thus, it is critical that factors leading to or ex...
24 Citations Source Cite
Markus W. Löffler8
Estimated H-index: 8
(University of Tübingen),
Heiko Schuster12
Estimated H-index: 12
(University of Tübingen)
+ 1 AuthorsStefan Beckert16
Estimated H-index: 16
(University of Tübingen)
Valid and reproducible sampling techniques as well as processing protocols are required for the assessment of biomarkers and mediators contained in wound exudate. Moreover, the ideal technique should be easy to use even in daily clinical routine. This is challenging since wound fluid represents an inhomogeneous mixture of different exogenous and endogenous sources. Analyzing wound fluid, however, may facilitate clinical decision making. Many techniques for obtaining wound fluid have been describ...
8 Citations Source Cite
Published on Jun 1, 2013in Biological Trace Element Research 2.36
Ursula Mirastschijski2
Estimated H-index: 2
(University of Bremen),
Alicia Martin1
Estimated H-index: 1
(Bispebjerg Hospital)
+ 2 AuthorsMagnus S. Ågren22
Estimated H-index: 22
(University of Copenhagen)
Trace element involvement in wounds left to heal by secondary intention needs clarification. We have previ- ously reported faster healing of wounds following acute surgery compared with elective excision of pilonidal sinus disease. The effect of topical zinc on the closure of the excisional wounds was mediocre compared with placebo. In contrast, parenteral zinc, copper, and selenium combined appear effective for wound healing in humans. We have investigated zinc, copper, and selenium with respec...
14 Citations Source Cite
Published on Apr 1, 2013in Molecular Immunology 3.19
Ying Sun2
Estimated H-index: 2
(University of Illinois at Chicago),
Yu Lu4
Estimated H-index: 4
(University of Illinois at Chicago)
+ 2 AuthorsHerve Y. Sroussi12
Estimated H-index: 12
(University of Illinois at Chicago)
Polymorphonuclear neutrophils (PMNs) produce and release copious amounts of reactive oxygen species (ROS) which target potential bacterial invaders but also contribute to the inflammation-associated organ injuries seen in sepsis. Calprotectin is an immune regulatory protein complex made of S100A8 and S100A9 that inhibits the oxidative metabolism of PMNs in vitro, an effect that can be potentiated by the controlled activation of the protease activated receptor-2 (PAR2). The aim of this study was ...
23 Citations Source Cite
Published on Aug 1, 2012in Journal of Clinical Investigation 13.25
J K Chan10
Estimated H-index: 10
,
J. Roth83
Estimated H-index: 83
+ 5 AuthorsJagdeep Nanchahal29
Estimated H-index: 29
Alarmins are endogenous molecules that are constitutively available and released upon tissue damage and activate the immune system. Current evidence indicates that uncontrolled and excessive release of alarmins contributes to the dysregulated processes seen in many inflammatory and autoimmune conditions, as well as tumorigenesis and cancer spread. Conversely, alarmins have also been found to play a major role in the orchestration of tissue homeostasis, including repair and remodeling in the hear...
236 Citations Source Cite
Published on Jan 1, 2013in Ulcers
Hannah Trøstrup5
Estimated H-index: 5
,
Thomas Bjarnsholt49
Estimated H-index: 49
+ 2 AuthorsClaus Moser36
Estimated H-index: 36
Chronic wounds are a growing socioeconomic problem in the western world. Knowledge on recalcitrant wounds relies on in vitro studies or clinical observations, and there is emerging evidence on the clinical impact of bacterial biofilm on skin healing. Chronic wounds are locked in the inflammatory state of wound healing, and there are multiple explanations for this arrest with the theory of exaggerated proteolysis as the most commonly accepted. Previously, there has not been enough focus on the di...
14 Citations Source Cite
Published on Feb 1, 2014in Diabetes 7.27
Ilham Bettahi2
Estimated H-index: 2
(Wayne State University),
Haijing Sun4
Estimated H-index: 4
(Wayne State University)
+ 5 AuthorsFu Shin X Yu34
Estimated H-index: 34
(Wayne State University)
Patients with diabetes mellitus (DM) may develop corneal complications and delayed wound healing. The aims of this study are to characterize the molecular signatures and biological pathways leading to delayed epithelial wound healing and to delineate the involvement of TGFβ3 therein. Genome-wide cDNA microarray analysis revealed 1,888 differentially expressed genes in the healing epithelia of normal (NL) versus type 1 DM rat corneas. Gene ontology and enrichment analyses indicated TGFβ signaling...
18 Citations Source Cite
Published on Jul 1, 2014in Expert Review of Molecular Diagnostics 3.33
Ferdinando Mannello29
Estimated H-index: 29
,
Daniela Ligi8
Estimated H-index: 8
+ 1 AuthorsJoseph D. Raffetto28
Estimated H-index: 28
(Brigham and Women's Hospital)
Chronic venous disease represents a healthcare problem due to high prevalence and recurrence rates. Studies on chronic venous ulcer wound fluid (CVUWF) have demonstrated increased inflammation and proteolysis which can cause tissue destruction and delayed healing. This review discusses: nearly all known metabolites discovered in the past 25 years in CVUWF studies; the omics approaches characterizing the microenvironment of human venous leg ulcers; and the use of biocompounds as prognostic biomar...
16 Citations Source Cite
A. Halawi1
Estimated H-index: 1
(American University of Beirut),
Ossama Abbas16
Estimated H-index: 16
(American University of Beirut),
Meera Mahalingam23
Estimated H-index: 23
(Boston University)
The structurally related, low-molecular weight S100 proteins constitute a family of proteins that possess a common basic structure allowing them to carry out a range of intracellular and extracellular functions. Unifying intracellular functions relate to regulation of proliferation, energy metabolism, calcium homeostasis, enzyme activities, cell growth and differentiation. Extracellular tasks, however, appear somewhat specific to select S100 members and include participation in innate and adapti...
8 Citations Source Cite
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