Cytokines and Venous Leg Ulcer Healing-A Systematic Review

Ewa A Burian, Lubna Sabah, Tonny Karlsmark, Klaus Kirketerp-Møller, Christine J Moffatt, Jacob P Thyssen, Magnus S Ågren, Ewa A Burian, Lubna Sabah, Tonny Karlsmark, Klaus Kirketerp-Møller, Christine J Moffatt, Jacob P Thyssen, Magnus S Ågren

Abstract

Venous leg ulcers (VLUs) are the most common type of leg ulcers with a significant socioeconomic burden due to slow healing. Cytokines may be involved in the pathogenesis of VLUs. In this systematic review, our objective was to investigate the association between cytokine levels, including growth factors, with the healing of VLUs. PubMed, Embase, Web of Science and Cochrane Library were searched from their inception to August 2021. We retrieved 28 articles investigating 38 different cytokines in 790 patients. Cytokines were most commonly investigated in wound fluid and less frequently in biopsies and serum. The studies were judged as having a moderate to high risk of bias, and the results were often inconsistent and sometimes conflicting. A meta-analysis was not performed due to clinical and methodological heterogeneities. We found weak evidence for elevated IL-1α, IL-6, IL-8, TNF-α and VEGF levels in non-healing VLUs, an elevation that declined with healing. TGF-β1 levels tended to increase with VLU healing. Other cytokines warranting further investigations include EGF, FGF-2, GM-CSF, IL-1β, IL-1Ra and PDGF-AA/PDGF-BB. We conclude that non-healing VLUs may be associated with an elevation of a palette of pro-inflammatory cytokines, possibly reflecting activated innate immunity in these wounds. There is a paucity of reliable longitudinal studies monitoring the dynamic changes in cytokine levels during wound healing.

Keywords: biomarker; chronic wound; cytokine; growth factor; inflammation; wound healing.

Conflict of interest statement

No company or organization had any role in the design of the study; in the collection, analyses or interpretation of data; in the writing of the manuscript or in the decision to publish the results. Reponex Pharmaceuticals sponsors E.A.B. in her PhD through payments to the department outside the submitted work. E.A.B. is an investigator for Reponex Pharmaceuticals, investigating the effect of topical GM-CSF in VLUs in an RCT. E.A.B has been an investigator for clinical research for Genentech, Reapplix, Ilkos therapeutic and SoftOx Solutions outside the submitted work. C.J.M. is sponsored by Thuasne and Essity Healthcare for consulting in compression therapy and by the International Lymphoedema Framework for work on different research outside the submitted work. T.K. is sponsored by Coloplast regarding stomas and wound healing as part of an advisory board membership, has been an investigator for Genentech and is a medical advisor for Reponex Pharmaceuticals outside the submitted work. K.K.M. has received honorary for lecturing from Novo Nordisk and AstraZeneca and has a patent licensed by SoftOx Solutions as well as shares. L.S., M.S.Å. and J.T.P. have no conflicts of interest related to this study.

Figures

Figure 1
Figure 1
PRISMA flow diagram [39].
Figure 2
Figure 2
Quality assessment of the 28 included studies (risk of bias). The individual studies were judged in six domains (D1–D6), and each domain was judged as high, moderate or low risk of bias. An overall rating took all domains into account. The traffic-light plot was created with a tool by McGuinness et al. [70].
Figure 3
Figure 3
Elevated cytokines (p < 0.10) shown in at least three studies in this review.

References

    1. Nelzén O., Bergqvist D., Lindhagen A. Venous and non-venous leg ulcers: Clinical history and appearance in a population study. Br. J. Surg. 1994;81:182–187. doi: 10.1002/bjs.1800810206.
    1. Margolis D.J., Bilker W., Santanna J., Baumgarten M. Venous leg ulcer: Incidence and prevalence in the elderly. J. Am. Acad. Dermatol. 2002;46:381–386. doi: 10.1067/mjd.2002.121739.
    1. Guest J.F., Fuller G.W., Vowden P. Cohort study evaluating the burden of wounds to the UK’s National Health Service in 2017/2018: Update from 2012/2013. BMJ Open. 2020;10:e045253. doi: 10.1136/bmjopen-2020-045253.
    1. Van den Oever R., Hepp B., Debbaut B., Simon I. Socio-economic impact of chronic venous insufficiency. An underestimated public health problem. Int. Angiol. 1998;17:161–167.
    1. Gottrup F., Henneberg E., Trangbaek R., Baekmark N., Zøllner K., Sørensen J. Point prevalence of wounds and cost impact in the acute and community setting in Denmark. J. Wound Care. 2013;22:413–422. doi: 10.12968/jowc.2013.22.8.413.
    1. Olsson M., Järbrink K., Divakar U., Bajpai R., Upton Z., Schmidtchen A., Car J. The humanistic and economic burden of chronic wounds: A systematic review. Wound Repair. Regen. 2019;27:114–125. doi: 10.1111/wrr.12683.
    1. Menke N.B., Ward K.R., Witten T.M., Bonchev D.G., Diegelmann R.F. Impaired wound healing. Clin. Dermatol. 2007;25:19–25. doi: 10.1016/j.clindermatol.2006.12.005.
    1. Gottrup F., Apelqvist J., Price P. Outcomes in controlled and comparative studies on non-healing wounds: Recommendations to improve the quality of evidence in wound management. J. Wound Care. 2010;19:237–268. doi: 10.12968/jowc.2010.19.6.48471.
    1. Eming S.A., Martin P., Tomic-Canic M. Wound repair and regeneration: Mechanisms, signaling, and translation. Sci. Transl. Med. 2014;6:265sr266. doi: 10.1126/scitranslmed.3009337.
    1. Nelson E.A., Bell-Syer S.E. Compression for preventing recurrence of venous ulcers. Cochrane Database Syst. Rev. 2014;9:CD002303. doi: 10.1002/14651858.CD002303.pub3.
    1. O’Meara S., Cullum N., Nelson E.A., Dumville J.C. Compression for venous leg ulcers. Cochrane Database Syst. Rev. 2012;11:CD000265. doi: 10.1002/14651858.CD000265.pub3.
    1. Shi C., Dumville J.C., Cullum N., Connaughton E., Norman G. Compression bandages or stockings versus no compression for treating venous leg ulcers. Cochrane Database Syst. Rev. 2021;7:CD013397. doi: 10.1002/14651858.CD013397.
    1. Gohel M.S., Taylor M., Earnshaw J.J., Heather B.P., Poskitt K.R., Whyman M.R. Risk factors for delayed healing and recurrence of chronic venous leg ulcers—An analysis of 1324 legs. Eur. J. Vasc. Endovasc. Surg. 2005;29:74–77. doi: 10.1016/j.ejvs.2004.10.002.
    1. Guest M., Smith J.J., Sira M.S., Madden P., Greenhalgh R.M., Davies A.H. Venous ulcer healing by four-layer compression bandaging is not influenced by the pattern of venous incompetence. Br. J. Surg. 1999;86:1437–1440. doi: 10.1046/j.1365-2168.1999.01288.x.
    1. Murphy K., Weaver C. 9th ed. Garland Science; New York, NY, USA: Taylor & Francis Group; Oxfordshire, UK: 2017. Janeway’s Immunobiology.
    1. Dinarello C.A. Historical insights into cytokines. Eur. J. Immunol. 2007;37((Suppl. 1)):S34–S45. doi: 10.1002/eji.200737772.
    1. Miyajima A., Kitamura T., Harada N., Yokota T., Arai K. Cytokine receptors and signal transduction. Annu. Rev. Immunol. 1992;10:295–331. doi: 10.1146/annurev.iy.10.040192.001455.
    1. Zlotnik A. Perspective: Insights on the nomenclature of cytokines and chemokines. Front. Immunol. 2020;11:908. doi: 10.3389/fimmu.2020.00908.
    1. Stenken J.A., Poschenrieder A.J. Bioanalytical chemistry of cytokines—A review. Anal. Chim. Acta. 2015;853:95–115. doi: 10.1016/j.aca.2014.10.009.
    1. Liu C., Chu D., Kalantar-Zadeh K., George J., Young H.A., Liu G. Cytokines: From clinical significance to quantification. Adv. Sci. 2021;8:e2004433. doi: 10.1002/advs.202004433.
    1. Commins S.P., Borish L., Steinke J.W. Immunologic messenger molecules: Cytokines, interferons, and chemokines. J. Allergy Clin. Immunol. 2010;125:S53–S72. doi: 10.1016/j.jaci.2009.07.008.
    1. Landén N.X., Li D., Ståhle M. Transition from inflammation to proliferation: A critical step during wound healing. Cell. Mol. Life Sci. 2016;73:3861–3885. doi: 10.1007/s00018-016-2268-0.
    1. Nuutila K., Siltanen A., Peura M., Bizik J., Kaartinen I., Kuokkanen H., Nieminen T., Harjula A., Aarnio P., Vuola J., et al. Human skin transcriptome during superficial cutaneous wound healing. Wound Repair Regen. 2012;20:830–839. doi: 10.1111/j.1524-475X.2012.00831.x.
    1. Vogt P.M., Lehnhardt M., Wagner D., Jansen V., Krieg M., Steinau H.U. Determination of endogenous growth factors in human wound fluid: Temporal presence and profiles of secretion. Plast. Reconstr. Surg. 1998;102:117–123. doi: 10.1097/00006534-199807000-00018.
    1. Rennekampff H.O., Hansbrough J.F., Kiessig V., Dore C., Sticherling M., Schröder J.M. Bioactive interleukin-8 is expressed in wounds and enhances wound healing. J. Surg. Res. 2000;93:41–54. doi: 10.1006/jsre.2000.5892.
    1. Nogueira B.C.F., Campos A.K., Alves R.S., Sarandy M.M., Novaes R.D., Esposito D., Gonçalves R.V. What is the impact of depletion of immunoregulatory genes on wound healing? A systematic review of preclinical evidence. Oxid. Med. Cell. Longev. 2020;2020:8862953. doi: 10.1155/2020/8862953.
    1. McFarland-Mancini M.M., Funk H.M., Paluch A.M., Zhou M., Giridhar P.V., Mercer C.A., Kozma S.C., Drew A.F. Differences in wound healing in mice with deficiency of IL-6 versus IL-6 receptor. J. Immunol. 2010;184:7219–7228. doi: 10.4049/jimmunol.0901929.
    1. Gallucci R.M., Simeonova P.P., Matheson J.M., Kommineni C., Guriel J.L., Sugawara T., Luster M.I. Impaired cutaneous wound healing in interleukin-6-deficient and immunosuppressed mice. FASEB J. 2000;14:2525–2531. doi: 10.1096/fj.00-0073com.
    1. Fang Y., Gong S.J., Xu Y.H., Hambly B.D., Bao S. Impaired cutaneous wound healing in granulocyte/macrophage colony-stimulating factor knockout mice. Br. J. Dermatol. 2007;157:458–465. doi: 10.1111/j.1365-2133.2007.07979.x.
    1. Ågren M.S., Gottrup F. Causation of venous leg ulcers. In: Morison M.J., Moffatt C.J., Franks P.J., editors. Leg Ulcers: A Problem-Based Learning Approach. Mosby; Edinburgh, UK: 2007. pp. 141–154.
    1. Mansilha A., Sousa J. Pathophysiological mechanisms of chronic venous disease and implications for venoactive drug therapy. Int. J. Mol. Sci. 2018;19:1669. doi: 10.3390/ijms19061669.
    1. Liu Y.C., Margolis D.J., Isseroff R.R. Does inflammation have a role in the pathogenesis of venous ulcers? A critical review of the evidence. J. Invest. Dermatol. 2011;131:818–827. doi: 10.1038/jid.2010.428.
    1. Trengove N.J., Bielefeldt-Ohmann H., Stacey M.C. Mitogenic activity and cytokine levels in non-healing and healing chronic leg ulcers. Wound Repair Regen. 2000;8:13–25. doi: 10.1046/j.1524-475x.2000.00013.x.
    1. Loots M.A., Lamme E.N., Zeegelaar J., Mekkes J.R., Bos J.D., Middelkoop E. Differences in cellular infiltrate and extracellular matrix of chronic diabetic and venous ulcers versus acute wounds. J. Invest. Dermatol. 1998;111:850–857. doi: 10.1046/j.1523-1747.1998.00381.x.
    1. Trøstrup H., Lundquist R., Christensen L.H., Jorgensen L.N., Karlsmark T., Haab B.B., Ågren M.S. S100A8/A9 deficiency in nonhealing venous leg ulcers uncovered by multiplexed antibody microarray profiling. Br. J. Dermatol. 2011;165:292–301. doi: 10.1111/j.1365-2133.2011.10384.x.
    1. Beidler S.K., Douillet C.D., Berndt D.F., Keagy B.A., Rich P.B., Marston W.A. Inflammatory cytokine levels in chronic venous insufficiency ulcer tissue before and after compression therapy. J. Vasc. Surg. 2009;49:1013–1020. doi: 10.1016/j.jvs.2008.11.049.
    1. Harris I.R., Yee K.C., Walters C.E., Cunliffe W.J., Kearney J.N., Wood E.J., Ingham E. Cytokine and protease levels in healing and non-healing chronic venous leg ulcers. Exp. Dermatol. 1995;4:342–349. doi: 10.1111/j.1600-0625.1995.tb00058.x.
    1. Burian E.A., Franks P.J., Moffatt C.J., Kirketerp-Møller K., Karlsmark T., Thyssen J.P., Ågren M.S. The Role of Cytokines and Growth Factors as Biomarkers for Wound Healing in Venous Leg Ulcers—A Systematic Review. [(accessed on 1 April 2022)]. Available online: .
    1. Page M.J., McKenzie J.E., Bossuyt P.M., Boutron I., Hoffmann T.C., Mulrow C.D., Shamseer L., Tetzlaff J.M., Akl E.A., Brennan S.E., et al. The PRISMA 2020 statement: An updated guideline for reporting systematic reviews. BMJ. 2021;372:n71. doi: 10.1136/bmj.n71.
    1. Hayden J.A., van der Windt D.A., Cartwright J.L., Côté P., Bombardier C. Assessing bias in studies of prognostic factors. Ann. Intern. Med. 2013;158:280–286. doi: 10.7326/0003-4819-158-4-201302190-00009.
    1. Hayden J.A., Wilson M.N., Riley R.D., Iles R., Pincus T., Ogilvie R. Individual recovery expectations and prognosis of outcomes in non-specific low back pain: Prognostic factor review. Cochrane Database Syst. Rev. 2019;9:CD011284. doi: 10.1002/14651858.CD011284.pub2.
    1. Westby M.J., Dumville J.C., Stubbs N., Norman G., Wong J.K., Cullum N., Riley R.D. Protease activity as a prognostic factor for wound healing in venous leg ulcers. Cochrane Database Sys. Rev. 2018;9:CD012841. doi: 10.1002/14651858.CD012841.pub2.
    1. Charles C.A., Tomic-Canic M., Vincek V., Nassiri M., Stojadinovic O., Eaglstein W.H., Kirsner R.S. A gene signature of nonhealing venous ulcers: Potential diagnostic markers. J. Am. Acad. Dermatol. 2008;59:758–771. doi: 10.1016/j.jaad.2008.07.018.
    1. Drinkwater S.L., Burnand K.G., Ding R., Smith A. Increased but ineffectual angiogenic drive in nonhealing venous leg ulcers. J. Vasc. Surg. 2003;38:1106–1112. doi: 10.1016/S0741-5214(03)01053-X.
    1. Escandon J., Vivas A.C., Perez R., Kirsner R., Davis S. A prospective pilot study of ultrasound therapy effectiveness in refractory venous leg ulcers. Int. Wound J. 2012;9:570–578. doi: 10.1111/j.1742-481X.2011.00921.x.
    1. Filkor K., Németh T., Nagy I., Kondorosi É., Urbán E., Kemény L., Szolnoky G. 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. Int. Wound J. 2016;13:554–562. doi: 10.1111/iwj.12473.
    1. Fivenson D.P., Faria D.T., Nickoloff B.J., Poverini P.J., Kunkel S., Burdick M., Strieter R.M. Chemokine and inflammatory cytokine changes during chronic wound healing. Wound Repair Regen. 1997;5:310–322. doi: 10.1046/j.1524-475X.1997.50405.x.
    1. Gohel M.S., Windhaber R.A., Tarlton J.F., Whyman M.R., Poskitt K.R. The relationship between cytokine concentrations and wound healing in chronic venous ulceration. J. Vasc. Surg. 2008;48:1272–1277. doi: 10.1016/j.jvs.2008.06.042.
    1. Grandi V., Bacci S., Corsi A., Sessa M., Puliti E., Murciano N., Scavone F., Cappugi P., Pimpinelli N. ALA-PDT exerts beneficial effects on chronic venous ulcers by inducing changes in inflammatory microenvironment, especially through increased TGF-beta release: A pilot clinical and translational study. Photodiagn. Photodyn. Ther. 2018;21:252–256. doi: 10.1016/j.pdpdt.2017.12.012.
    1. He C.F., Cherry G.W., Arnold F. Postural vasoregulation and mediators of reperfusion injury in venous ulceration. J. Vasc. Surg. 1997;25:647–653. doi: 10.1016/S0741-5214(97)70290-8.
    1. Hodde J.P., Hiles M.C., Metzger D.W. Characterization of the local wound environment following treatment of chronic leg ulcers with SIS wound matrix. J. Tissue Viability. 2020;29:42–47. doi: 10.1016/j.jtv.2019.12.003.
    1. Krejner A., Litwiniuk M., Grzela T. LL-37 but not 25-hydroxy-vitamin D serum level correlates with healing of venous leg ulcers. Arch. Immunol. Ther. Exp. 2017;65:455–461. doi: 10.1007/s00005-016-0423-9.
    1. Lagattolla N.R., Stacey M.C., Burnand K.G., Gaffney P.G. Growth factors, tissue and urokinase-type plasminogen activators in venous ulcers. Ann. Cardiol. Angeiol. 1995;44:299–303.
    1. Ligi D., Mosti G., Croce L., Raffetto J.D., Mannello F. Chronic venous disease—Part I: Inflammatory biomarkers in wound healing. Biochim. Biophys. Acta. 2016;1862:1964–1974. doi: 10.1016/j.bbadis.2016.07.018.
    1. Ligi D., Croce L., Mosti G., Raffetto J.D., Mannello F. Chronic venous insufficiency: Transforming growth factor-beta isoforms and soluble endoglin concentration in different states of wound healing. Int. J. Mol. Sci. 2017;18:2206. doi: 10.3390/ijms18102206.
    1. McQuilling J.P., Carter M.J., Fulton J.A., Patel K., Doner B., Serena T.E., Mowry K.C. A prospective clinical trial evaluating changes in the wound microenvironment in patients with chronic venous leg ulcers treated with a hypothermically stored amniotic membrane. Int. Wound J. 2021 doi: 10.1111/iwj.13606.
    1. Murphy M.A., Joyce W.P., Condron C., Bouchier-Hayes D. A reduction in serum cytokine levels parallels healing of venous ulcers in patients undergoing compression therapy. Eur. J. Vasc. Endovasc. Surg. 2002;23:349–352. doi: 10.1053/ejvs.2002.1597.
    1. Mwaura B., Mahendran B., Hynes N., Defreitas D., Avalos G., Adegbola T., Adham M., Connolly C.E., Sultan S. The impact of differential expression of extracellular matrix metalloproteinase inducer, matrix metalloproteinase-2, tissue inhibitor of matrix metalloproteinase-2 and PDGF-AA on the chronicity of venous leg ulcers. Eur. J. Vasc. Endovasc. Surg. 2006;31:306–310. doi: 10.1016/j.ejvs.2005.08.007.
    1. Pukstad B.S., Ryan L., Flo T.H., Stenvik J., Moseley R., Harding K., Thomas D.W., Espevik T. Non-healing is associated with persistent stimulation of the innate immune response in chronic venous leg ulcers. J. Dermatol. Sci. 2010;59:115–122. doi: 10.1016/j.jdermsci.2010.05.003.
    1. Sadler G.M., Wallace H.J., Stacey M.C. Oral doxycycline for the treatment of chronic leg ulceration. Arch. Dermatol. Res. 2012;304:487–493. doi: 10.1007/s00403-011-1201-5.
    1. Senet P., Bon F.X., Benbunan M., Bussel A., Traineau R., Calvo F., Dubertret L., Dosquet C. Randomized trial and local biological effect of autologous platelets used as adjuvant therapy for chronic venous leg ulcers. J. Vasc. Surg. 2003;38:1342–1348. doi: 10.1016/S0741-5214(03)00908-X.
    1. Serra R., Grande R., Buffone G., Gallelli L., De Franciscis S. The effects of minocycline on extracellular matrix in patients with chronic venous leg ulcers. Acta Phlebol. 2013;14:99–107.
    1. Serra R., Gallelli L., Buffone G., Molinari V., Stillitano D.M., Palmieri C., de Franciscis S. Doxycycline speeds up healing of chronic venous ulcers. Int. Wound J. 2015;12:179–184. doi: 10.1111/iwj.12077.
    1. Stacey M.C., Phillips S.A., Farrokhyar F., Swaine J.M. Evaluation of wound fluid biomarkers to determine healing in adults with venous leg ulcers: A prospective study. Wound Repair Regen. 2019;27:509–518. doi: 10.1111/wrr.12723.
    1. Tian Y.W., Stacey M.C. Cytokines and growth factors in keratinocytes and sweat glands in chronic venous leg ulcers. An immunohistochemical study. Wound Repair Regen. 2003;11:316–325. doi: 10.1046/j.1524-475X.2003.11502.x.
    1. Wallace H.J., Stacey M.C. Levels of tumor necrosis factor-alpha (TNF-alpha) and soluble TNF receptors in chronic venous leg ulcers--correlations to healing status. J. Invest. Dermatol. 1998;110:292–296. doi: 10.1046/j.1523-1747.1998.00113.x.
    1. Wiegand C., Bittenger K., Galiano R.D., Driver V.R., Gibbons G.W. Does noncontact low-frequency ultrasound therapy contribute to wound healing at the molecular level? Wound Repair Regen. 2017;25:871–882. doi: 10.1111/wrr.12595.
    1. Serra R., Grande R., Buffone G., Molinari V., Perri P., Perri A., Amato B., Colosimo M., de Franciscis S. Extracellular matrix assessment of infected chronic venous leg ulcers: Role of metalloproteinases and inflammatory cytokines. Int. Wound J. 2016;13:53–58. doi: 10.1111/iwj.12225.
    1. McInnes R.L., Cullen B.M., Hill K.E., Price P.E., Harding K.G., Thomas D.W., Stephens P., Moseley R. Contrasting host immuno-inflammatory responses to bacterial challenge within venous and diabetic ulcers. Wound Repair Regen. 2014;22:58–69. doi: 10.1111/wrr.12133.
    1. McGuinness L.A., Higgins J.P.T. Risk-of-bias VISualization (robvis): An R package and Shiny web app for visualizing risk-of-bias assessments. Res. Synth. Methods. 2020;12:55–61. doi: 10.1002/jrsm.1411.
    1. Carvalho M.R., Silveira I.A., Oliveira B. Treatment of venous ulcers with growth factors: Systematic review and meta-analysis. Rev. Bras. Enferm. 2019;72:200–210. doi: 10.1590/0034-7167-2017-0865.
    1. Lee Y., Lee M.H., Phillips S.A., Stacey M.C. Growth factors for treating chronic venous leg ulcers: A systematic review and meta-analysis. Wound Repair Regen. 2022;30:117–125. doi: 10.1111/wrr.12982.
    1. Kantor J., Margolis D.J. A multicentre study of percentage change in venous leg ulcer area as a prognostic index of healing at 24 weeks. Br. J. Dermatol. 2000;142:960–964. doi: 10.1046/j.1365-2133.2000.03478.x.
    1. Cardinal M., Eisenbud D.E., Phillips T., Harding K. Early healing rates and wound area measurements are reliable predictors of later complete wound closure. Wound Repair Regen. 2008;16:19–22. doi: 10.1111/j.1524-475X.2007.00328.x.
    1. Marston W.A., Ennis W.J., Lantis J.C., 2nd, Kirsner R.S., Galiano R.D., Vanscheidt W., Eming S.A., Malka M., Cargill D.I., Dickerson J.E., Jr., et al. Baseline factors affecting closure of venous leg ulcers. J. Vasc. Surg. Venous Lymphat. Disord. 2017;5:829–835.e821. doi: 10.1016/j.jvsv.2017.06.017.
    1. Grimstad Ø., Sandanger Ø., Ryan L., Otterdal K., Damaas J.K., Pukstad B., Espevik T. Cellular sources and inducers of cytokines present in acute wound fluid. Wound Repair Regen. 2011;19:337–347. doi: 10.1111/j.1524-475X.2011.00668.x.
    1. Bao P., Kodra A., Tomic-Canic M., Golinko M.S., Ehrlich H.P., Brem H. The role of vascular endothelial growth factor in wound healing. J. Surg. Res. 2009;153:347–358. doi: 10.1016/j.jss.2008.04.023.
    1. Ambrosch A., Lobmann R., Pott A., Preissler J. Interleukin-6 concentrations in wound fluids rather than serological markers are useful in assessing bacterial triggers of ulcer inflammation. Int. Wound J. 2008;5:99–106. doi: 10.1111/j.1742-481X.2007.00347.x.
    1. Zillmer R., Trøstrup H., Karlsmark T., Ifversen P., Ågren M.S. Duration of wound fluid secretion from chronic venous leg ulcers is critical for interleukin-1α, interleukin-1β, interleukin-8 levels and fibroblast activation. Arch. Dermatol. Res. 2011;303:601–606. doi: 10.1007/s00403-011-1164-6.
    1. Nylander-Lundqvist E., Egelrud T. Formation of active IL-1 beta from pro-IL-1 beta catalyzed by stratum corneum chymotryptic enzyme in vitro. Acta Derm. Venereol. 1997;77:203–206.
    1. Baggiolini M., Dewald B., Moser B. Interleukin-8 and related chemotactic cytokines–CXC and CC chemokines. Adv. Immunol. 1994;55:97–179.
    1. Krzyszczyk P., Schloss R., Palmer A., Berthiaume F. The role of macrophages in acute and chronic wound healing and interventions to promote pro-wound healing phenotypes. Front. Physiol. 2018;9:419. doi: 10.3389/fphys.2018.00419.
    1. Shapouri-Moghaddam A., Mohammadian S., Vazini H., Taghadosi M., Esmaeili S.A., Mardani F., Seifi B., Mohammadi A., Afshari J.T., Sahebkar A. Macrophage plasticity, polarization, and function in health and disease. J. Cell. Physiol. 2018;233:6425–6440. doi: 10.1002/jcp.26429.
    1. Tecchio C., Micheletti A., Cassatella M.A. Neutrophil-derived cytokines: Facts beyond expression. Front. Immunol. 2014;5:508. doi: 10.3389/fimmu.2014.00508.
    1. Wilgus T.A., Roy S., McDaniel J.C. Neutrophils and wound repair: Positive actions and negative reactions. Adv. Wound Care. 2013;2:379–388. doi: 10.1089/wound.2012.0383.
    1. Cañedo-Dorantes L., Cañedo-Ayala M. Skin acute wound healing: A comprehensive review. Int. J. Inflam. 2019;2019:3706315. doi: 10.1155/2019/3706315.
    1. Piipponen M., Li D., Landén N.X. The immune functions of keratinocytes in skin wound healing. Int. J. Mol. Sci. 2020;21:8790. doi: 10.3390/ijms21228790.
    1. Kondo T., Ohshima T., Eisenmenger W. Immunohistochemical and morphometrical study on the temporal expression of interleukin-1alpha (IL-1alpha) in human skin wounds for forensic wound age determination. Int. J. Legal Med. 1999;112:249–252. doi: 10.1007/s004140050244.
    1. Pulido T., Velarde M.C., Alimirah F. The senescence-associated secretory phenotype: Fueling a wound that never heals. Mech. Ageing Dev. 2021;199:111561. doi: 10.1016/j.mad.2021.111561.
    1. Short W.D., Wang X., Keswani S.G. The role of T lymphocytes in cutaneous scarring. Adv. Wound Care. 2022;11:121–131. doi: 10.1089/wound.2021.0059.
    1. Sachdev U., Vodovotz L., Bitner J., Barclay D., Zamora R., Yin J., Simmons R.L., Vodovotz Y. Suppressed networks of inflammatory mediators characterize chronic venous insufficiency. J. Vasc. Surg. Venous Lymphat. Disord. 2018;6:358–366. doi: 10.1016/j.jvsv.2017.11.009.
    1. Herrick S.E., Sloan P., McGurk M., Freak L., McCollum C.N., Ferguson M.W. Sequential changes in histologic pattern and extracellular matrix deposition during the healing of chronic venous ulcers. Am. J. Pathol. 1992;141:1085–1095.
    1. Bosanquet D.C., Rangaraj A., Richards A.J., Riddell A., Saravolac V.M., Harding K.G. Topical steroids for chronic wounds displaying abnormal inflammation. Ann. R. Coll. Surg. Engl. 2013;95:291–296. doi: 10.1308/003588413X13629960045634.
    1. Hofman D., Moore K., Cooper R., Eagle M., Cooper S. Use of topical corticosteroids on chronic leg ulcers. J. Wound Care. 2007;16:227–230. doi: 10.12968/jowc.2007.16.5.27047.
    1. Fox J.D., Baquerizo-Nole K.L., Keegan B.R., Macquhae F., Escandon J., Espinosa A., Perez C., Romanelli P., Kirsner R.S. Adalimumab treatment leads to reduction of tissue tumor necrosis factor-alpha correlated with venous leg ulcer improvement: A pilot study. Int. Wound J. 2016;13:963–966. doi: 10.1111/iwj.12497.
    1. Streit M., Beleznay Z., Braathen L.R. Topical application of the tumour necrosis factor-alpha antibody infliximab improves healing of chronic wounds. Int. Wound J. 2006;3:171–179. doi: 10.1111/j.1742-481X.2006.00233.x.
    1. Bootun R. Effects of immunosuppressive therapy on wound healing. Int. Wound J. 2013;10:98–104. doi: 10.1111/j.1742-481X.2012.00950.x.
    1. Tekin H.G., Eskandarani H.A., Iversen L., Juel J. Immunosuppressive therapy and post-operative wound healing. Ugeskr. Laeger. 2021;183:V07200544.
    1. Yang Z.P., Hong L., Wu Q., Wu K.C., Fan D.M. Preoperative infliximab use and postoperative complications in Crohn’s disease: A systematic review and meta-analysis. Int. J. Surg. 2014;12:224–230. doi: 10.1016/j.ijsu.2013.12.015.
    1. Parameswaran N., Patial S. Tumor necrosis factor-α signaling in macrophages. Crit. Rev. Eukaryot. Gene Expr. 2010;20:87–103. doi: 10.1615/CritRevEukarGeneExpr.v20.i2.10.
    1. Brooklyn T.N., Dunnill M.G., Shetty A., Bowden J.J., Williams J.D., Griffiths C.E., Forbes A., Greenwood R., Probert C.S. Infliximab for the treatment of pyoderma gangrenosum: A randomised, double blind, placebo controlled trial. Gut. 2006;55:505–509. doi: 10.1136/gut.2005.074815.
    1. Ashcroft G.S., Jeong M.J., Ashworth J.J., Hardman M., Jin W., Moutsopoulos N., Wild T., McCartney-Francis N., Sim D., McGrady G., et al. Tumor necrosis factor-alpha (TNF-α) is a therapeutic target for impaired cutaneous wound healing. Wound Repair Regen. 2012;20:38–49. doi: 10.1111/j.1524-475X.2011.00748.x.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다