Cited by 223Diagnosis and Treatment of Venous DiseasesWound Healing and TreatmentsLymphatic System and Diseases

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Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

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Beidler, Stephanie K., Douillet, Christelle D., Berndt, Daniel F., Keagy, Blair A., Rich, Preston B., Marston, William A.·2009·Journal of Vascular Surgery

DOI 10.1016/j.jvs.2008.11.049PMC PMC4710545

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Abstract

Objective Elevated inflammatory cytokine levels have been implicated in the pathogenesis of non-healing chronic venous insufficiency (CVI) ulcers. The goal of this study was to determine the protein levels of a wide range of inflammatory cytokines in untreated CVI ulcer tissue before and after 4 weeks of high-strength compression therapy. These levels were compared to cytokines present in healthy tissue.Methods Thirty limbs with untreated CVI and leg ulceration received therapy for 4 weeks with sustained high-compression bandaging at an ambulatory wound center. Biopsies were obtained from healthy and ulcerated tissue before and after therapy. A multiplexed protein assay was used to measure multiple cytokines in a single sample. Patients were designated as rapid or delayed healers based on ulcer surface area change.Results The majority of pro-inflammatory cytokine protein levels were elevated in ulcer tissue compared to healthy tissue, and compression therapy significantly reduced these cytokines. TGF-beta1 was upregulated in ulcer tissue following compression therapy. Rapid healing ulcers had significantly higher levels of IL-1alpha, IL-1beta, IFN-gamma, IL-12p40, and granulocyte macrophage colony stimulating factor (GM-CSF) before compression therapy, and IL-1 Ra after therapy. IFN-gamma levels significantly decreased following therapy in the rapidly healing patients.Conclusion CVI ulcer healing is associated with a pro-inflammatory environment prior to treatment that reflects metabolically active peri-wound tissue that has the potential to heal. Treatment with compression therapy results in healing that is coupled with reduced pro-inflammatory cytokine levels and higher levels of the anti-inflammatory cytokine IL-1 Ra.

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BackgroundInfluential
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Cytokines and Venous Leg Ulcer Healing—A Systematic Review
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“Beidler 2009 [36] 29 Cohort 4 weeks Biopsy Luminex, ELISA G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL12p40, IL-12p70, IL-13, IL-15, IL-17, TGF-β1, TNF-α”
BackgroundInfluential
S100A8/A9 deficiency in nonhealing venous leg ulcers uncovered by multiplexed antibody microarray profiling
Trøstrup, H., Lundquist, R., Christensen, L. H., Jørgensen, L. N., Karlsmark, T., Haab, B. B., & Ågren, M. S. (2011) · British Journal of Dermatology · doi:10.1111/j.1365-2133.2011.10384.x · Cited by 49
Using a diagnostic tool to identify elevated protease activity levels in chronic and stalled wounds: a consensus panel discussion.
Snyder, R., Driver, V. R., Fife, C. E., Lantis, J. C., Peirce, B., Serena, T. E., & Weir, D. (2011) · PubMed · Cited by 45
Acceleration of chronic wound healing by bio-inorganic polyphosphate: In vitro studies and first clinical applications
Schepler, H., Neufurth, M., Wang, S., She, Z., Schröder, H. C., Wang, X., & Müller, W. E. G. (2021) · Theranostics · doi:10.7150/thno.67148 · Cited by 44
“impaired inflammatory cytokine levels, vessel insufficiencies (venous or arterial insufficiencies) are involved in the pathogenesis of non-healing chronic wounds [46].”
Background
Proteomics in chronic wound research: Potentials in healing and health
Broadbent, J. A., Walsh, T., & Upton, Z. (2010) · PROTEOMICS - CLINICAL APPLICATIONS · doi:10.1002/prca.200900152 · Cited by 44
“Dysregulation in the presentation of vascular endothelial growth factor [57, 65, 97], epithelial growth factor [98], hepatocyte growth factor [99], platelet-derived growth factor [82], transforming growth factor-b1 [65, 81, 87, 93, 98, 100, 101], transforming growth factor-b2 [100, 102] and insulin-like growth factor-…”
Background
Medical management of venous ulcers
Pascarella, L. E., & Shortell, C. K. (2015) · Seminars in Vascular Surgery · doi:10.1053/j.semvascsurg.2015.06.001 · Cited by 41
“In the same study, the concentration of interleukin 1Ra, an inhibitor of the proinflammatory effect of interleukin 1β, was increased after 4 weeks of compression therapy [14].”
BackgroundInfluential
Tissue Bioanalysis of Biotherapeutics And Drug Targets to Support Pk/Pd
Neubert, H., Fountain, S. T., King, L., Clark, T. H., Weng, Y., O’Hara, D. M., Li, W., Leung, S. S., RAY, C. A., Palandra, J., et al. (2012) · Bioanalysis · doi:10.4155/bio.12.234 · Cited by 40
Chemokine‐Capturing Wound Contact Layer Rescues Dermal Healing
Schirmer, L., Atallah, P., Freudenberg, U., & Werner, C. (2021) · Advanced Science · doi:10.1002/advs.202100293 · Cited by 42
Fibroblast-like cells Promote Wound Healing via PD-L1-mediated Inflammation Resolution
Wang, X., Guo, W., Qiu, W., Ao, L., Yao, M., Xing, W., Yu, Y., Chen, Q., Wu, X., Li, Z., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.69890 · Cited by 35
“It has reported that chronic wound tissue and fluid indicate a continual competition between inflammatory and anti-inflammatory signals leading to a misbalanced environment for proper wound healing to occur, which delays the wound healing [10, 11].”
Background
Venous Ulcer: What Is New?
Raffetto, J. D., & Marston, W. A. (2011) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0b013e3181fcaff2 · Cited by 35
Self-citation
Compression therapy in leg ulcers
Partsch, H. (2013) · Reviews in vascular medicine · doi:10.1016/j.rvm.2013.02.001 · Cited by 34
Global Perspective on Diabetic Foot Ulcerations
Dinh, T. (2011) · InTech eBooks · doi:10.5772/1173 · Cited by 34
Epidemiology and aetiology of C4–6 disease
Bradbury, A. W. (2010) · Phlebology The Journal of Venous Disease · doi:10.1258/phleb.2010.010s01 · Cited by 33
MDL‐800, the SIRT6 Activator, Suppresses Inflammation via the NF‐ κ B Pathway and Promotes Angiogenesis to Accelerate Cutaneous Wound Healing in Mice
Jiang, X., Yao, Z., Wang, K., Lou, L., Xue, K., Chen, J., Zhang, G., Zhang, Y. L., Du, J., Lin, C., et al. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/1619651 · Cited by 34
“TNF-α downregulation is likely to be responsible for such performance because the in ﬂ ammatory cytokines TNF-α can increase matrix metallo-proteinase (MMP) secretion and collagen degradation and suppress collagen I/III synthesis [23].”
The use of wound healing assessment methods in psychological studies: A review and recommendations
Koschwanez, H. E., & Broadbent, E. (2010) · British Journal of Health Psychology · doi:10.1348/135910710x524633 · Cited by 35
Biofilm and Equine Limb Wounds
Jørgensen, E., Bjarnsholt, T., & Jacobsen, S. E. (2021) · Animals · doi:10.3390/ani11102825 · Cited by 34
Harnessing Multifaceted Next-Generation Technologies for Improved Skin Wound Healing
Bhar, B., Chouhan, D., Pai, N., & Mandal, B. B. (2021) · ACS Applied Bio Materials · doi:10.1021/acsabm.1c00880 · Cited by 32
Xanthine Oxidoreductase: A Novel Therapeutic Target for the Treatment of Chronic Wounds?
Fernandez, M. L., Stupar, D., Croll, T. I., Leavesley, D. I., & Upton, Z. (2017) · Advances in Wound Care · doi:10.1089/wound.2016.0724 · Cited by 32
“7,20,21 IL-1 b is a potent mediator of inﬂam-mation and is elevated in wound ﬂuids and tissues from chronic venous leg ulcers.”
Influential
Wounds in chronic leg oedema
Burian, E. A., Karlsmark, T., Nørregaard, S., Kirketerp‐Møller, K., Kirsner, R. S., Franks, P. J., Quéré, I., & Moffatt, C. J. (2021) · International Wound Journal · doi:10.1111/iwj.13642 · Cited by 29
Simple wound exudate collection method identifies bioactive cytokines and chemokines in (arterio) venous ulcers
Kroeze, K. L., Vink, L., Boer, E. M. D., Scheper, R. J., van Montfrans, C., & Gibbs, S. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2012.00789.x · Cited by 28
Fabrication of carboxymethylcellulose hydrogel containing β-cyclodextrin–eugenol inclusion complexes for promoting diabetic wound healing
Li, M., Li, F., Wang, T., Zhao, L., & Shi, Y. (2019) · Journal of Biomaterials Applications · doi:10.1177/0885328219873254 · Cited by 26
Evidenz der Kompressionstherapie
Konschake, W., Valesky, E. M., Stege, H., & Jünger, M. (2017) · Der Hautarzt · doi:10.1007/s00105-017-3999-z · Cited by 25
Latest Innovations in the Treatment of Venous Disease
Attaran, R. (2018) · Journal of Clinical Medicine · doi:10.3390/jcm7040077 · Cited by 24
“Venous ulcer levels of inflammatory cytokines IL-1 and interferon-γ fall with compression therapy [39].”
Background
Proteomics and Metabolomics forIn SituMonitoring of Wound Healing
Kalkhof, S., Förster, Y., Schmidt, J. R., Schulz, M. C., Baumann, S., Weißflog, A., Gao, W., Hempel, U., Eckelt, U., Rammelt, S., et al. (2014) · BioMed Research International · doi:10.1155/2014/934848 · Cited by 25
“In the last years, several proteins, especially inflammatory mediators, growth factors and cytokines [3, 4], proteases [5, 6], and oxidative stress related proteins [7, 8], were identified in WF which can be used to characterize and classify the effect on different phases of the wound healing process and thereby can b…”
Background
The application of L-PRP in AIDS patients with crural chronic ulcers: A pilot study
Cieslik-Bielecka, A., Skowroński, R., Jędrusik-Pawłowska, M., & Pierchała, M. (2017) · Advances in Medical Sciences · doi:10.1016/j.advms.2017.10.002 · Cited by 23
The effect of Mindfulness-Based Stress Reduction on wound healing: a preliminary study
Meesters, A., Meevissen, Y. M. C., Weijzen, C. A. H., Buurman, W. A., Losen, M. H., Schepers, J., Thissen, M. R. T. M., Alberts, H. J. E. M., Schalkwijk, C. G., & Peters, M. L. (2017) · Journal of Behavioral Medicine · doi:10.1007/s10865-017-9901-8 · Cited by 24
“Excessive inflammation delays wound healing; indeed higher concentrations of pro-inflammatory cytokines have been found in chronic wounds (Beidler et al. 2009).”
Background
Which dressings reduce inflammation and improve venous leg ulcer healing
Raffetto, J. D. (2014) · Phlebology The Journal of Venous Disease · doi:10.1177/0268355514529225 · Cited by 21
“In addition, as the VLU healed the level of the anti-inflammatory cytokine IL-1 Ra increased at 4 weeks following compression.(9) The importance of this study was to demonstrate the inflammatory and anti-inflammatory cytokines present in VLU, and how compression therapy is able to modulate the expression and promote V…”
BackgroundInfluential
Selective release of cytokines, chemokines, and growth factors by minced skin in vitro supports the effectiveness of autologous minced micrografts technique for chronic ulcer repair
Pertusi, G., Tiberio, R., Graziola, F., Boggio, P. S., Colombo, E., & Bozzo, C. (2012) · Wound Repair and Regeneration · doi:10.1111/j.1524-475x.2011.00762.x · Cited by 21
“Thus, inflammation, which is crucial in the early phase of wound healing, should resolve to accelerate recovery.(2,6,10,11) Venous insufficiency accounts for 75% of chronic leg ulcers.”
Background
Compression therapy in venous diseases: physical assumptions and clinical effects
Berszakiewicz, A., Sieroń, A., Krasiński, Z., Cholewka, A., & Stanek, A. (2019) · Advances in Dermatology and Allergology · doi:10.5114/ada.2019.86990 · Cited by 21
Chronic Venous Disease of the Lower Extremities: A State-of-the Art Review
Attaran, R., & Carr, J. G. (2022) · Journal of the Society for Cardiovascular Angiography & Interventions · doi:10.1016/j.jscai.2022.100538 · Cited by 23
The expression of inflammatory cytokines, TAM tyrosine kinase receptors and their ligands is upregulated in venous leg ulcer patients: a novel insight into chronic wound immunity
Filkor, K., Németh, T., Nagy, I., Kondorosi, É., Urbán, E. Z., Kemény, L. V., & Szolnoky, G. (2015) · International Wound Journal · doi:10.1111/iwj.12473 · Cited by 20
“Clinical studies in wound healing mostly focus on local alterations of inflammatory cytokine expressions (9); however, a novel study found that infected wounds produced an upregulation of circulating inflammatory cytokine pattern compared with non-infected ones (8).”
Background
Metabolites of the Nitric Oxide (NO) Pathway Are Altered and Indicative of Reduced NO and Arginine Bioavailability in Patients with Cardiometabolic Diseases Complicated with Chronic Wounds of Lower Extremities: Targeted Metabolomics Approach (LC-MS/MS)
Krzystek‐Korpacka, M., Wiśniewski, J. Ł., Fleszar, M. G., Bednarz-Misa, I. S., Bronowicka-Szydełko, A., Gacka, M., Masłowski, L., Kędzior, K., Witkiewicz, W., & Gamian, A. (2019) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2019/5965721 · Cited by 20
Myeloid Cells in Cutaneous Wound Repair
Cash, J. L., & Martin, P. B. (2016) · Microbiology Spectrum · doi:10.1128/microbiolspec.mchd-0017-2015 · Cited by 20
Compression Therapy Is Not Contraindicated in Diabetic Patients with Venous or Mixed Leg Ulcer
Mosti, G. B., Cavezzi, A., Bastiani, L., & Partsch, H. (2020) · Journal of Clinical Medicine · doi:10.3390/jcm9113709 · Cited by 18
“In addition, a positive effect on inflammatory cytokines was demonstrated as compression is able to decrease the inflammatory mediators and increase their antagonists [9,10].”
Background
Modalities to Treat Venous Ulcers: Compression, Surgery, and Bioengineered Tissue
Gould, L. J., Dosi, G., Couch, K. S., Gibbons, G. W., Howell, R. S., Brem, H., & Tomic‐Canic, M. (2016) · Plastic & Reconstructive Surgery · doi:10.1097/prs.0000000000002677 · Cited by 18
Leg ulceration in venous and arteriovenous insufficiency: assessment and management with compression therapy as part of a holistic wound‑healing strategy
Nair, H. K. R., Mosti, G. B., Atkin, L., Aburn, R., Hussin, N. A., Naresh, G., Narayanan, S., Ritchie, G., Samuriwo, R., Sandy‐Hodgetts, K., et al. (2024) · Journal of Wound Care · doi:10.12968/jowc.2024.33.sup10b.s1 · Cited by 17
Glycocalyx disruption, endothelial dysfunction and vascular remodeling as underlying mechanisms and treatment targets of chronic venous disease
Diaz, J. A., Gianesini, S., & Khalil, R. A. (2025) · International Angiology · doi:10.23736/s0392-9590.24.05339-2 · Cited by 22
Preparation of W/O Hypaphorine–Chitosan Nanoparticles and Its Application on Promoting Chronic Wound Healing via Alleviating Inflammation Block
Qi, M., Zhu, X., Yu, X., Ai, M., Cai, W., Du, B., Hou, B., & Qiu, L. (2021) · Nanomaterials · doi:10.3390/nano11112830 · Cited by 16
What is the Medical Rationale for the Treatment of Varicose Veins?
Meissner, M. H. (2012) · Phlebology The Journal of Venous Disease · doi:10.1258/phleb.2012.012s17 · Cited by 15
A dual compression system: preliminary clinical insights from the US
Lantis, J. C., Barrett, C., Couch, K. S., Ehmann, S., Greenstein, E., Ostler, M., & Tickner, A. (2020) · Journal of Wound Care · doi:10.12968/jowc.2020.29.sup9.s29 · Cited by 14
Association of autologous punch grafting, TLC-NOSF dressing and multitype compression therapy to rapidly achieve wound closure in hard-to-heal venous leg ulcers
Conde‐Montero, E., Bohbot, S., Sanz, R. G., Vázquez, A. P., Marín, L. R., Jerónimo, L. P., Sánchez, J. L. G., & de la Cueva, P. (2020) · JMV-Journal de Médecine Vasculaire · doi:10.1016/j.jdmv.2020.10.123 · Cited by 14
Theory and Practice of Compression Therapy for Treating and Preventing Venous Ulcers
Montero, E. C., Perrucho, N. S., & Dobao, P. D. L. C. (2020) · Actas Dermo-Sifiliográficas · doi:10.1016/j.adengl.2020.10.022 · Cited by 14
Impact of chronic wounds of various etiology on systemic profiles of key inflammatory cytokines, chemokines and growth factors, and their interplay
Krzystek‐Korpacka, M., Kędzior, K., Masłowski, L., Mierzchała-Pasierb, M., Bednarz‐Misa, I., Bronowicka-Szydełko, A., Kubiak, J., Gacka, M., Płaczkowska, S., & Gamian, A. (2019) · Advances in Clinical and Experimental Medicine · doi:10.17219/acem/103845 · Cited by 14

Authors: Beidler, S. K., Douillet, C. D., Berndt, D. F., Keagy, B. A., Rich, P. B., & Marston, W. A.
Affiliations: University of North Carolina at Chapel Hill (US)
Corresponding author: Marston, William A.
ORCID: Berndt, Daniel F.
Marston, William A.
Venue: Journal of Vascular Surgery
Publisher: Elsevier BV
Published: 2009-04
Volume: 49
Issue: 4
Pages: 1013-1020
ISSN: 0741-5214 (ISSN-L)
DOI: 10.1016/j.jvs.2008.11.049
PMC: PMC4710545
OpenAlex: W2048226370
Cited by: 223
References: 46
Citations by year: 2026: 12 · 2025: 10 · 2024: 17 · 2023: 17 · 2022: 21 · 2021: 21 · 2020: 16 · 2019: 11 · 2018: 14 · 2017: 16 · 2016: 13 · 2015: 9 · 2014: 11 · 2013: 7 · 2012: 11
FWCI: 9.10
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/legal/tdmrep-license (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 1568 d)
doi.org/10.15223/policy-017 (stm-asf)
doi.org/10.15223/policy-037 (stm-asf)
doi.org/10.15223/policy-012 (stm-asf)
doi.org/10.15223/policy-029 (stm-asf)
doi.org/10.15223/policy-004 (stm-asf)
Locations: Journal of Vascular Surgery (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
Funders: National Institute of General Medical Sciences (5 T32GM00845013)
National Institutes of Health
Topics: Health Sciences › Medicine › Surgery › Diagnosis and Treatment of Venous Diseases
Health Sciences › Medicine › Surgery › Wound Healing and Treatments
Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
Keywords: chronic venous insufficiency, leg ulcers, compression therapy, inflammatory cytokines, ulcer healing, TGF-β1, interleukin-1, interferon-gamma, interleukin-1 receptor antagonist, GM-CSF, IL-12
MeSH terms: Adult, Aged, Chronic Disease, Female, Humans, Male, Middle Aged, Time Factors, Varicose Ulcer, Venous Insufficiency, Wound Healing, Cytokines, Treatment Outcome, Inflammation Mediators, Stockings, Compression

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Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy

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