Cytokines and Venous Leg Ulcer Healing—A Systematic Review
Abstract
:1. Introduction
2. Materials and Methods
2.1. Study Types
2.2. Target Population
2.3. Cytokines Selected for the Search
2.4. Search Strategy
2.5. Data Collection and Extraction
2.6. Risk of Bias (Quality) Assessment
2.7. Measures of Association, Data Synthesis and Pooling of Data
2.8. Missing Data
3. Results
3.1. Characteristics of Included Studies and Participants
3.2. Collection of Specimen, Analysis, and Processing
3.3. Definitions of Healing
3.4. Cytokines in Non-Healing/Healing VLUs
3.5. Influence of Background Factors on Cytokine Levels
3.5.1. Compression Therapy
3.5.2. Other Factors
3.6. Bioactivity of Cytokines and Cytokine Receptors
3.7. Quality Assessment of Included Studies
4. Discussion
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
ABPI | ankle-brachial pressure index |
cDNA | complementary DNA |
EGF | epidermal growth factor |
ELISA | enzyme-linked immunosorbent assay |
FGF | fibroblast growth factor |
G-CSF | granulocyte colony-stimulating factor |
GM-CSF | granulocyte-macrophage colony-stimulating factor |
HB-EGF | heparin-binding epidermal growth factor |
HGF | hepatocyte growth factor |
IFN | interferon |
IGF | insulin-like growth factor |
IHC | immunohistochemistry |
IL | interleukin |
IL-1Ra | interleukin-1 receptor antagonist |
KGF | keratinocyte growth factor |
M-CSF | macrophage colony-stimulating factor |
NA | not applicable |
NGF | nerve growth factor |
NR | not reported |
PBMC | peripheral blood mononuclear cells |
PDGF | platelet-derived growth factor |
qRT-PCR | real-time quantitative reverse transcription polymerase chain reaction |
RCT | randomized controlled trial |
TGF | transforming growth factor |
TNF | tumor necrosis factor |
TNF-R | tumor necrosis factor receptor |
VEGF | vascular endothelial growth factor |
VEGF-R | vascular endothelial growth factor receptor |
VLU | venous leg ulcer |
WF | wound fluid |
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Author | N 1 | Study Type | Follow-Up Time | Specimen | Analysis | Cytokine 2 |
---|---|---|---|---|---|---|
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 |
Charles 2008 [43] | 10 | Cross-sectional | 0 | Biopsy | cDNA microarray | HB-EGF, PDGFRα, S100A7 |
Drinkwater 2003 [44] | 35 | Cohort | ~1 year | WF, biopsy | ELISA, RT-PCR | VEGF-121, VEGF-165, VEGF-189, VEGF-RI, VEGF-RII |
Escandon 2012 [45] | 10 | Clinical trial 3 | 4 weeks | Biopsy | RT-PCR | IL-1α, IL-6, IL-8, IL-10, IL-11, TNF-α, VEGF |
Filkor 2016 [46] | 69 | Cohort | 4 weeks | PBMC | qRT-PCR | IL-1α, IL-8, IL-10, TNF-α |
Fivenson 1997 [47] | 14 | Cohort | 8 weeks | WF | ELISA | IL-8, IL-10 |
Gohel 2008 [48] | 80 | Cohort | 5 weeks | WF, serum | ELISA | FGF-2, IL-1β, TGF-β1, TNF-α, VEGF |
Grandi 2018 [49] | 19 | Clinical trial 4 | ~3 weeks | Biopsy | IHC | TGF-β, TNF-α |
Harris 1995 [37] | 18 | Cross-sectional | 0 | WF | ELISA, bioassay | FGF-2, GM-CSF, IL-1α, IL-1α bio, IL-1β bio, IL-6 bio, PDGF-AB |
He 1997 [50] | 10 | Experimental 5 | 200 min | Serum | ELISA | IL-1β, IL-1Ra, IL-6, TNF-α |
Hodde 2020 [51] | 12 | Clinical trial 6 | 12 weeks | WF | Luminex, ELISA | GM-CSF, IFN-γ, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12(p70), IL-13, TGF-β1, TNF-α |
Krejner 2017 [52] | 19 | Cohort, retrospective | -4 weeks | Serum | ELISA | IL-6, IL-8, TNF |
Lagattolla 1995 [53] | 19 | Cohort 7 | 6 months | Biopsy | ELISA | FGF-2, PDGF-AB, TGF-β1, |
Ligi 2016 [54] | 34 | Cross-sectional, cohort | During admission | WF | Luminex | FGF-2, G-CSF, GM-CSF, IFN-γ, IL-1β, IL-1Ra, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12(p70), IL-13, IL-15, IL-17, PDGF-BB, TNF-α, VEGF |
Ligi 2017 [55] | 30 | Cross-sectional, cohort | 0 | WF | Luminex | TGF-β1, TGF-β2, TGF-β3 |
McQuilling 2021 [56] | 15 | Clinical trial 8 | 12 weeks | WF | Multiplex MAP arrays | EGF, FGF-2, G-CSF, GM-CSF, IFN-γ, IL-1α, IL-1β, IL-1Ra, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL-15, IL-17, PDGF-AA, PDGF-BB, TGF-α, TGF-β1, TGF-β2, TGF-β3, TNF-α, TNF-β, VEGF |
Murphy 2002 [57] | 8 | Cohort | 12 weeks | Serum | ELISA | TNF-α, VEGF |
Mwaura 2006 [58] | 40 | Cohort | 8 weeks | WF, biopsy | ELISA, IHC | PDGF-AA |
Pukstad 2010 [59] | 8 | Cohort | 8 weeks | WF | Antibody array, bioassay | IL-1α, IL-1β, IL-6R, IL-8, TNF-α, sTNF-RI, sTNF-RII |
Sadler 2012 [60] | 20 | Clinical trial 9 | 4 weeks | WF | ELISA | TNF-α |
Senet 2003 [61] | 15 | RCT 10 | 16 weeks | WF | ELISA | IL-8, KGF, VEGF |
Serra 2013 [62] | 60 | RCT 11 | ~13 months | WF, plasma | ELISA | VEGF |
Serra 2015 [63] | 64 | RCT 9 | ~13 months | WF, plasma | ELISA | VEGF |
Stacey 2019 [64] | 42 | Cohort | 13 weeks | WF | Multiplex 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, IL-11, IL-12p40, IL-12p70, IL-13, IL-15, IL-16, IL-17, M-CSF, PDGF-BB, TNF-α, TNF-β, TNF-RI, TNF-RII |
Tian 2003 [65] | 21 | Cohort | 2 weeks | Biopsy | IHC | EGF, FGF-2, IL-1α, IL-6, PDGF-A, TGF-β1, TNF-α, TNF-RI, VEGF |
Trengove 2000 [33] | 26 | Cohort | 2 weeks | WF | ELISA, bioassay | EGF, FGF-2, IL-1α, IL-1β, IL-1 bio, IL-6, IL-6 bio, TGF-β1, TNF-α, PDGF |
Wallace 1998 [66] | 21 | Cohort | 2 weeks | WF | ELISA, bioassay | TNF-α, TNF-α bio, sTNF-RI, sTNF-RII |
Wiegand 2017 [67] | 42 | RCT 12 | 4 weeks | WF, biopsy | Luminex, IHC | IL-1β, IL-6, IL-8, IL-10, TGF-β, TNF-α |
Cytokine | Non-Healing VLUs | vs. | Healing VLUs |
---|---|---|---|
EGF | ↑ Biopsy [65] | ↑ WF [56] | |
FGF-2 | ↑ Biopsy [65] | ↑ Biopsy [53] | |
GM-CSF | ↑ WF [54,64] | ↑ Biopsy [36] 1 | |
HB-EGF | ↑ Biopsy [43] | ||
IFN-γ | ↑ Biopsy [36] 1 | ||
IL-1α | ↑ WF [33,56], ↑ Biopsy [45,65], ↑ Blood [46] | ↑ Biopsy [36] 1 | |
IL-1β | ↑ WF [33,54] | ↑ Biopsy [36] 1 | |
IL-1 bio 3 | ↑ WF [33] | ||
IL-1Ra | ↑ WF [56] | ↑ Biopsy [36] 2 | |
IL-2 | ↑ WF [56] | ||
IL-3 | ↑ WF [56] | ||
IL-6 | ↑ WF [67], ↑ Biopsy [45,65] | ↑ WF [64] 4 | |
IL-6 bio 3 | ↑ WF [33] | ||
IL-7 | ↑ WF [56] | ||
IL-8 | ↑ WF [51,54,56,61], ↑ Biopsy [45], ↑ Blood [46] | ↑ WF [47] | |
IL-9 | ↑ WF [56] | ||
IL-10 | ↑ WF [54] | ||
IL-11 | ↑ Biopsy [45] | ||
IL-12p40 | ↑ Biopsy [36] 1 | ||
IL-12p70 | ↑ WF [54] | ||
IL-16 | ↑ WF [64] 4 | ||
PDGF-AA | ↑ Biopsy [65] | ↑ WF [58], ↑ Biopsy [58] | |
PDGF-BB | ↑ WF [54,64] 4 | ||
PDGFRα | ↑ Biopsy [43] | ||
S100A7 | ↑ Biopsy [43] | ||
TGF-β1 | ↑ Biopsy [65] | ↑ WF [48,51], ↑ Biopsy [49,53] | |
TGF-β3 | ↑ WF [55] | ||
TNF-α | ↑ WF [33,51,66], ↑ Biopsy [45,65], ↑ Blood [57] 2 | ||
TNF-β | ↑ WF [56] | ||
TNF-RI | ↑ Biopsy [65] | ||
TNF-RII | ↑ WF [66] | ||
VEGF | ↑ WF [44,54,62,63], ↑ Biopsy [45,65], ↑ Blood [57,62,63] 2 |
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Burian, E.A.; Sabah, L.; Karlsmark, T.; Kirketerp-Møller, K.; Moffatt, C.J.; Thyssen, J.P.; Ågren, M.S. Cytokines and Venous Leg Ulcer Healing—A Systematic Review. Int. J. Mol. Sci. 2022, 23, 6526. https://doi.org/10.3390/ijms23126526
Burian EA, Sabah L, Karlsmark T, Kirketerp-Møller K, Moffatt CJ, Thyssen JP, Ågren MS. Cytokines and Venous Leg Ulcer Healing—A Systematic Review. International Journal of Molecular Sciences. 2022; 23(12):6526. https://doi.org/10.3390/ijms23126526
Chicago/Turabian StyleBurian, Ewa A., Lubna Sabah, Tonny Karlsmark, Klaus Kirketerp-Møller, Christine J. Moffatt, Jacob P. Thyssen, and Magnus S. Ågren. 2022. "Cytokines and Venous Leg Ulcer Healing—A Systematic Review" International Journal of Molecular Sciences 23, no. 12: 6526. https://doi.org/10.3390/ijms23126526