AccScience Publishing / ITPS / Online First / DOI: 10.36922/itps.2241
Submit to ITPS
Cite this article
49
Download
1131
Views
Journal Browser
Volume | Year
Issue
Search
Forthcoming Issue
Current Issue
View All
News and Announcements
View All
ORIGINAL RESEARCH ARTICLE

The effect of dapsone on skin flap survival depends on modulation of inflammatory response and VEGF expression

Abolfazl Badripour1,2,3 ,  Anahita Najafi1,4 ,  Zahra Ebrahim Soltani1,2 ,  Alireza Hasanzadeh1,4 ,  Mohamad Behzadi5 ,  Alireza Rahbar1,4 ,  Armaghan Ahangarishizary1,4 ,  Seyed Mohsen Ahmadi-Tafti3,6 ,  Mohammad Ashouri3,6 ,  Ahmadreza Dehpour1,7*
Show Less
1 Experimental Medicine Research Center, Tehran University of Medical Sciences, Tehran, Iran
2 Brain and Spinal Cord Injury Research Center, Neuroscience Institute, Tehran University of Medical Sciences, Tehran, Iran
3 Colorectal Surgery Research Center, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
4 Department of Medicine, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
5 Department of Surgery, Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
6 Department of Surgery, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
7 Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
INNOSC Theranostics and Pharmacological Sciences 2024, 7(2), 2241 https://doi.org/10.36922/itps.2241
Submitted: 13 November 2023 | Accepted: 25 January 2024 | Published: 16 April 2024
© 2024 by the Author (s). This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution 4.0 International License ( https://creativecommons.org/licenses/by/4.0/ )
Download PDF
Cite
XML
Abstract

The random-pattern skin flap is a common method used for reconstructing skin defects. However, flap ischemia necrosis remains a significant challenge in plastic surgery. Strategies aimed at reducing persistent inflammation and promoting blood supply through angiogenesis have been identified as crucial for improving flap survival. Dapsone, a chemotherapeutic agent known for its anti-inflammatory properties through multiple pathways, is of interest in this regard. This study aims to investigate the effect of dapsone on random-pattern flap survival in rats, along with its impact on inflammation and angiogenesis. The ischemia/reperfusion (I/R) injury rat models were created using a caudal-based dorsal skin flap with delayed I/R. Twenty-four male Sprague Dawley rats were divided into control, sham, and two treatment groups receiving dapsone at doses of 12.5 mg/kg/day and 5 mg/kg/day, respectively. On the 7th post-operative day, flap survival was evaluated. Neutrophil infiltration and ulceration were measured through microscopic examination, and interleukin (IL)-8 levels through enzyme-linked immunosorbent assay. Expression levels of vascular endothelial growth factor (VEGF) and tumor necrosis factor-alpha (TNF-α) were determined using an immunohistochemistry (IHC) array. The findings revealed an increased flap survival on day 7 post-operation following systemic administration of dapsone for 5 consecutive days. Dapsone at both dosages significantly reduced the ulcer thickness, neutrophil infiltration, and IL-8 levels. The IHC results revealed that VEGF expression was significantly higher in the treatment groups compared to the control group. Moreover, TNF-α expression was significantly lower in the treatment groups compared to the control group. In conclusion, we confirmed that treatment with dapsone promotes skin flap survival, and this effect aligned with a reduction in persistent inflammation and the enhancement of VEGF. Nonetheless, more studies are required to elucidate the precise anti-inflammatory mechanism of dapsone in I/R injuries.

Keywords
Dapsone
Inflammation
Ischemia/reperfusion injury
Skin flap
VEGF
Funding
None.
Conflict of interest
The authors declare no conflict of interest.
References
  1. Basu G, Downey H, Guo S, et al. Prevention of distal flap necrosis in a rat random skin flap model by gene electro transfer delivering VEGF(165) plasmid. J Gene Med. 2014;16(3-4):55-65. doi: 10.1002/jgm.2759

 

  1. Pavletic MM. Skin flaps in reconstructive surgery. Vet Clin North Am Small Anim Pract. 1990;20(1):81-103. doi: 10.1016/s0195-5616(90)50005-4

 

  1. Kruter L, Rohrer T. Advancement flaps. Dermatol Surg. 2015;41:S239-S246. doi: 10.1097/DSS.0000000000000497

 

  1. Myers BM, Cherry G. Causes of necrosis in pedicle flaps. Plast Reconstr Surg. 1968;42(1):43-50.

 

  1. Callegari PR, Taylor GI, Caddy CM, Minabe T. An anatomic review of the delay phenomenon: I. Experimental studies. Plast Reconstr Surg. 1992;89(3):397-407; discussion 417-418.

 

  1. Du Z, Zan T, Li H, Li Q. A study of blood flow dynamics in flap delay using the full-field laser perfusion imager. Microvasc Res. 2011;82(3):284-290. doi: 10.1016/j.mvr.2011.09.010

 

  1. Taylor GI, Corlett RJ, Caddy CM, Zelt RG. An anatomic review of the delay phenomenon: II. Clinical applications. Plast Reconstr Surg. 1992;89(3):408-416; discussion 417-418.

 

  1. Luo X, Zhao B, Chen B, et al. Trans-cinnamaldehyde increases random pattern flap survival through activation of the nitric oxide pathway. Drug Des Devel Ther. 2021;15:679-688. doi: 10.2147/DDDT.S297458

 

  1. Lee JH, You HJ, Lee TY, Kang HJ. Current status of experimental animal skin flap models: Ischemic preconditioning and molecular factors. Int J Mol Sci. 2022;23(9):5234. doi: 10.3390/ijms23095234

 

  1. Khalil AA, Aziz FA, Hall JC. Reperfusion injury. Plast Reconstr Surg. 2006;117(3):1024-1033. doi: 10.1097/01.prs.0000204766.17127.54

 

  1. Suzuki S, Miyachi Y, Niwa Y, Isshiki N. Significance of reactive oxygen species in distal flap necrosis and its salvage with liposomal SOD. Br J Plast Surg. 1989;42(5):559-564. doi: 10.1016/0007-1226(89)90045-3

 

  1. Abbaszadeh-Kasbi A, Haddadi NS, Dehdashtian A, et al. Acute activation of α7-nicotinic receptors by nicotine improves rodent skin flap survival through nitrergic system. Ann Plast Surg. 2019;83(2):211-216. doi: 10.1097/sap.0000000000001809

 

  1. Wilgus TA, Roy S, McDaniel JC. Neutrophils and wound repair: Positive actions and negative reactions. Adv Wound Care (New Rochelle). 2013;2(7):379-388. doi: 10.1089/wound.2012.0383

 

  1. Tanno H, Kawakami K, Kanno E, et al. Invariant NKT cells promote skin wound healing by preventing a prolonged neutrophilic inflammatory response. Wound Repair Regen. 2017;25(5):805-815. doi: 10.1111/wrr.12588

 

  1. Lan CCE, Wu CS, Huang SM, Wu IH, Chen GS. High-glucose environment enhanced oxidative stress and increased interleukin-8 secretion from keratinocytes: New insights into impaired diabetic wound healing. Diabetes. 2013;62(7):2530-2538. doi: 10.2337/db12-1714

 

  1. Qazi BS, Tang K, Qazi A. Recent advances in underlying pathologies provide insight into interleukin-8 expression-mediated inflammation and angiogenesis. Int J Inflam. 2011;2011:908468. doi: 10.4061/2011/908468

 

  1. He JB, Fang MJ, Ma XY, Li WJ, Lin DS. Angiogenic and anti-inflammatory properties of azadirachtin A improve random skin flap survival in rats. Exp Biol Med (Maywood). 2020;245(18):1672-1682. doi: 10.1177/1535370220951896

 

  1. Fan W, Liu Z, Chen J, et al. Effect of memantine on the survival of an ischemic random skin flap and the underlying mechanism. Biomed Pharmacother. 2021;143:112163. doi: 10.1016/j.biopha.2021.112163

 

  1. Vourtsis SA, Papalois AE, Agrogiannis GD, Spyriounis PK, Patsouris E, Ionac M. Improvement of a long random skin flap survival by application of vascular endothelial growth factor in various ways of local administration in a rat model. Indian J Plast Surg. 2012;45(1):102-108. doi: 10.4103/0970-0358.96596

 

  1. Zhang F, Brooks D, Chen W, Mustain W, Chen MB, Lineaweaver WC. Improvement of venous flap survival by application of vascular endothelial growth factor in a rat model. Ann Plast Surg. 2006;56(6):670-673. doi: 10.1097/01.sap.0000203998.37851.57

 

  1. Qi C, Lin Y, Lin D. The effect of Shu Xue Tong treatment on random skin flap survival via the VEGF-Notch/Dll4 signaling pathway. J Invest Surg. 2020;33(7):615-620. doi: 10.1080/08941939.2018.1551948

 

  1. McCourt M, Wang JH, Sookhai S, Redmond HP. Proinflammatory mediators stimulate neutrophil-directed angiogenesis. Arch Surg. 1999;134(12):1325-1331; discussion 1331-1332. doi: 10.1001/archsurg.134.12.1325

 

  1. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;153(2):347-358. doi: 10.1016/j.jss.2008.04.023

 

  1. Anderson K, Hamm RL. Factors that impair wound healing. J Am Coll Clin Wound Spec. 2012;4(4):84-91. doi: 10.1016/j.jccw.2014.03.001

 

  1. Buttle GAH, Stephenson D, Smith S, Dewing T, Foster GE. The treatment of streptococcal infections in mice with 4:4’diaminodiphenylsulphone. Lancet. 1937;229:1331-1334. doi: 10.1016/S0140-6736(00)75868-5

 

  1. Ghaoui N, Hanna E, Abbas O, Kibbi AG, Kurban M. Update on the use of dapsone in dermatology. Int J Dermatol. 2020;59(7):787-795. doi: 10.1111/ijd.14761

 

  1. Harvath L, Yancey KB, Katz SI. Selective inhibition of human neutrophil chemotaxis to N-formyl-methionyl-leucyl-phenylalanine by sulfones. J Immunol. 1986;137(4):1305-1311.

 

  1. Debol SM, Herron MJ, Nelson RD. Anti-inflammatory action of dapsone: Inhibition of neutrophil adherence is associated with inhibition of chemoattractant-induced signal transduction. J Leukoc Biol. 1997;62(6):827-836. doi: 10.1002/jlb.62.6.827

 

  1. Abe M, Shimizu A, Yokoyama Y, Takeuchi Y, Ishikawa O. A possible inhibitory action of diaminodiphenyl sulfone on tumour necrosis factor-alpha production from activated mononuclear cells on cutaneous lupus erythematosus. Clin Exp Dermatol. 2008;33(6):759-763. doi: 10.1111/j.1365-2230.2008.02864.x

 

  1. Karpel-Massler G, Kast RE, Siegelin MD, et al. Anti-glioma activity of dapsone and its enhancement by synthetic chemical modification. Neurochem Res. 2017;42:3382-3389. doi: 10.1007/s11064-017-2378-6

 

  1. Wang C, Cai Y, Zhang Y, Xiong Z, Li G, Cui L. Local injection of deferoxamine improves neovascularization in ischemic diabetic random flap by increasing HIF-1α and VEGF expression. PLoS One. 2014;9(6):e100818. doi: 10.1371/journal.pone.0100818

 

  1. Jafari RM, Shayesteh S, Ala M, et al. Dapsone ameliorates colitis through TLR4/NF-kB pathway in TNBS induced colitis model in rat. Archi Med Res. 2021;52(6):595-602. doi: 10.1016/j.arcmed.2021.03.005

 

  1. Rashidian A, Rashki A, Abdollahi A, et al. Dapsone reduced acetic acid-induced inflammatory response in rat colon tissue through inhibition of NF-kB signaling pathway. Immunopharmacol Immunotoxicol. 2019;41(6):607-613. doi: 10.1080/08923973.2019.1678635

 

  1. Deng C, Wu B, Wei Z, Zhang Z, Zhang T, Wang D. A systematic study of vascular distribution characteristics and axis design of various flap types. Med Sci Monit. 2019;25:721-729. doi: 10.12659/MSM.911940

 

  1. McFarlane R, Deyoung G, Henry RA. The design of a pedicle flap in the rat to study necrosis and its prevention. Plast Reconstr Surg. 1965;35(2):177-182. doi: 10.1097/00006534-196502000-00007

 

  1. Van den Heuvel MGW, Buurman WA, Bast A, van der Hulst RRW. Review: Ischaemia-reperfusion injury in flap surgery. J Plast Reconstr Aesthet Surg. 2009;62(6):721-726. doi: 10.1016/j.bjps.2009.01.060

 

  1. Aryannejad A, Gandominejad A, Tabary M, et al. Protective effect of modafinil on skin flap survival in the experimental random-pattern skin flap model in rats: The role of ATP-sensitive potassium channels and nitric oxide pathway. J Plast Reconstr Aesthet Surg. 2021;74(6):1346-1354. doi: 10.1016/j.bjps.2020.10.084

 

  1. Tabary M, Aryannejad A, Noroozi N, et al. Ivermectin increases random-pattern skin flap survival in rats: The novel role of GABAergic system. J Surg Res. 2021;259:431-441. doi: 10.1016/j.jss.2020.09.010

 

  1. Im J, Kong TH, Choi JS, et al. Non-invasive postoperative monitoring of pedicled rat skin flap using laser speckle contrast imaging. Microvasc Res. 2020;132:10405. doi: 10.1016/j.mvr.2020.104050

 

  1. Cetinkale O, Bilgic L, Bolayirli M, Sengul R, Ayan F, Burcak G. Involvement of neutrophils in ischemia-reperfusion injury of inguinal island skin flaps in rats. Plast Reconstr Surg. 1998;102(1):153-160. doi: 10.1097/00006534-199807000-00024

 

  1. Donnahoo KK, Meng X, Ayala A, Cain MP, Harken AH, Meldrum DR. Early kidney TNF-alpha expression mediates neutrophil infiltration and injury after renal ischemia-reperfusion. Am J Physiol. 1999;277(3):R922-R929. doi: 10.1152/ajpregu.1999.277.3.R922

 

  1. Chen F, Wang D, Jiang Y, Ma H, Li X, Wang H. Dexmedetomidine postconditioning alleviates spinal cord ischemia-reperfusion injury in rats via inhibiting neutrophil infiltration, microglia activation, reactive gliosis and CXCL13/CXCR5 axis activation. Int J Neurosci. 2021;133:1-12. doi: 10.1080/00207454.2021.1881089

 

  1. Zhang P, Yue K, Liu X, et al. Endothelial Notch activation promotes neutrophil transmigration via downregulating endomucin to aggravate hepatic ischemia/reperfusion injury. Sci China Life Sci. 2020;63(3):375-387. doi: 10.1007/s11427-019-1596-4

 

  1. Perry BC, Soltys D, Toledo AH, Toledo-Pereyra LH. Tumor necrosis factor-α in liver ischemia/reperfusion injury. J Invest Surg. 2011;24(4):178-188. doi: 10.3109/08941939.2011.568594

 

  1. Wozel G, Blasum C. Dapsone in dermatology and beyond. Arch Dermatol Res. 2014;306(2):103-124. doi: 10.1007/s00403-013-1409-7

 

  1. Modschiedler K, Weller M, Wörl P, von den Driesch P. Dapsone and colchicine inhibit adhesion of neutrophilic granulocytes to epidermal sections. Arch Dermatol Res. 2000;292(1):32-36. doi: 10.1007/pl00007458

 

  1. Suda T, Suzuki Y, Matsui T, et al. Dapsone suppresses human neutrophil superoxide production and elastase release in a calcium-dependent manner. Br J Dermatol. 2005;152(5):887-895. doi: 10.1111/j.1365-2133.2005.06559.x

 

  1. Zalewska A, Napieralska-Krzysiek E. [Dapsone in skin diseases]. Pol Merkur Lekarsk. 2003;15(89):484-486.

 

  1. Khalilzadeh M, Shayan M, Jourian S, Rahimi M, Sheibani M, Dehpour AR. A comprehensive insight into the anti-inflammatory properties of dapsone. Naunyn Schmiedebergs Arch Pharmacol. 2022;395(12):1509-1523. doi: 10.1007/s00210-022-02297-1

 

  1. Kuhn A, Ruland V, Bonsmann G. Cutaneous lupus erythematosus: Update of therapeutic options part II. J Am Acad Dermatol. 2011;65(6):e195-e213. doi: 10.1016/j.jaad.2010.06.017

 

  1. Stannard JN, Kahlenberg JM. Cutaneous lupus erythematosus: Updates on pathogenesis and associations with systemic lupus. Curr Opin Rheumatol. 2016;28(5):453-459. doi: 10.1097/bor.0000000000000308

 

  1. Kozub P, Simaljakova M. Hidradenitis suppurativa treated with combination of infliximab and dapsone. Bratisl Lek Listy. 2012;113(5):319-323. doi: 10.4149/bll_2012_074

 

  1. Geyfman M, Debabov D, Poloso N, Alvandi N. Mechanistic insight into the activity of a sulfone compound dapsone on Propionibacterium (Newly Reclassified as Cutibacterium) Acnes-mediated cytokine production. Exp Dermatol. 2019;28(2):190-197. doi: 10.1111/exd.13869

 

  1. Köstler E, Wollina U. Ulcerated necrobiosis lipoidica: A combined treatment approach with dermatosurgery and PUVA. Int J Low Extrem Wounds. 2003;2(4):243-245. doi: 10.1177/1534734603260680

 

  1. Erfurt-Berge C, Heusinger V, Reinboldt-Jockenhöfer F, Dissemond J, Renner R. Comorbidity and therapeutic approaches in patients with necrobiosis lipoidica. Dermatology. 2022;238:148-155. doi: 10.1159/000514687

 

  1. Kwon MJ, Joo HG. Dapsone modulates lipopolysaccharide-activated bone marrow cells by inducing cell death and down-regulating tumor necrosis factor-α production. J Vet Sci. 2018;19(6):744-749. doi: 10.4142/jvs.2018.19.6.744

 

  1. Nezamoleslami S, Sheibani M, Jahanshahi F, Mumtaz F, Abbasi A, Dehpour AR. Protective effect of dapsone against renal ischemia-reperfusion injury in rat. Immunopharmacol Immunotoxicol. 2020;42(3):272-279. doi: 10.1080/08923973.2020.1755308

 

  1. Sheibani M, Nezamoleslami S, Faghir-Ghanesefat H, Emami AH, Dehpour AR. Cardioprotective effects of dapsone against doxorubicin-induced cardiotoxicity in rats. Cancer Chemother Pharmacol. 2020;85(3):563-571. doi: 10.1007/s00280-019-04019-6

 

  1. Kast RE, Lefranc F, Karpel-Massler G, Halatsch ME. Why dapsone stops seizures and may stop neutrophils’ delivery of VEGF to glioblastoma. Br J Neurosurg. 2012;26(6):813-817. doi: 10.3109/02688697.2012.674577

 

  1. Kast RE. Dapsone as treatment adjunct in ARDS. Exp Lung Res. 2020;46(5):157-161. doi: 10.1080/01902148.2020.1753266

 

  1. Kast RE, Hill QA, Wion D, et al. Glioblastoma-synthesized G-CSF and GM-CSF contribute to growth and immunosuppression: Potential therapeutic benefit from dapsone, fenofibrate, and ribavirin. Tumour Biol. 2017;39(5):1010428317699797. doi: 10.1177/1010428317699797

 

  1. Qian LW, Fourcaudot AB, Yamane K, You T, Chan RK, Leung KP. Exacerbated and prolonged inflammation impairs wound healing and increases scarring. Wound Repair Regen. 2016;24(1):26-34. doi: 10.1111/wrr.12381

 

  1. Ellis S, Lin EJ, Tartar D. Immunology of wound healing. Curr Dermatol Rep. 2018;7(4):350-358. doi: 10.1007/s13671-018-0234-9

 

  1. Harder Y, Amon M, Laschke M, et al. An old dream revitalised: Preconditioning strategies to protect surgical flaps from critical ischaemia and ischaemia-reperfusion injury. J Plast Reconstr Aesthet Surg. 2008;61(5):503-511. doi: 10.1016/j.bjps.2007.11.032

 

  1. Hosnuter M, Babucçu O, Kargi E, Altinyazar C. Dual preconditioning: Effects of pharmacological plus ischemic preconditioning on skin flap survival. Ann Plast Surg. 2003;50(4):398-402. doi: 10.1097/01.SAP.0000037261.84618.7F

 

  1. Gözü A, Poda M, Taskin EI, et al. Pretreatment with octreotide modulates iNOS gene expression, mimics surgical delay, and improves flap survival. Ann Plast Surg. 2010;65(2):245-249. doi: 10.1097/SAP.0b013e3181c1fe8f
Share
Back to top
INNOSC Theranostics and Pharmacological Sciences, Electronic ISSN: 2705-0823 Print ISSN: 2705-0734, Published by AccScience Publishing
We use cookies on our website to ensure you get the best experience.
Read more about our cookies here
Accept