The Role of Proinflammatory Cytokine GM-CSF as A Therapy for Diabetic Ulcers: A Systematic Review
Abstract
Diabetic ulcers represent a prevalent complication among patients with poorly controlled diabetes mellitus, often resulting from inadequate blood glucose regulation, neuropathy, peripheral artery disease, and suboptimal wound care. This systematic review aims to evaluate the therapeutic efficacy of granulocyte-macrophage colony-stimulating factor (GM-CSF) for diabetic ulcers. The review utilized databases such as PubMed, ProQuest, and Google Scholar, with only six articles meeting the eligibility criteria for analysis. The findings suggest that GM-CSF exhibits therapeutic potential by enhancing neovascularization, promoting keratinocyte proliferation, facilitating granulation tissue formation, and reducing wound diameter. These results highlight the potential of GM-CSF as a therapeutic agent for diabetic ulcers. Nevertheless, the current body of research is limited, necessitating further studies with larger populations and diverse GM-CSF administration methods to substantiate these findings.
References
Agrawal, R. P., Agrawal, S., Beniwal, S., Joshi, C. P., & Kochar, D. K. (2003). Granulocyte- macrophage colony- stimulating factor in foot ulcers. 6(2), 93–97.
Akkus, G., & Sert, M. (2022). Diabetic foot ulcers: A devastating complication of diabetes mellitus continues non-stop in spite of new medical treatment modalities. World Journal of Diabetes, 13(12), 1106–1121. https://doi.org/10.4239/wjd.v13.i12.1106
Armstrong, D. G., Boulton, A. J. M., & Bus, S. A. (2017). Diabetic Foot Ulcers and Their Recurrence. New England Journal of Medicine, 376(24), 2367–2375. https://doi.org/10.1056/nejmra1615439
Armstrong, D. G., Tan, T.-W., Boulton, A. J. M., & Bus, S. A. (2023). Diabetic Foot Ulcers: A Review. JAMA, 330(1), 62–75. https://doi.org/10.1001/jama.2023.10578
Briganti, S., Mosca, S., Di Nardo, A., Flori, E., & Ottaviani, M. (2024). New Insights into the Role of PPARγ in Skin Physiopathology. Biomolecules, 14(6), 728. https://doi.org/10.3390/biom14060728
Burgess, J. L., Wyant, W. A., Abdo Abujamra, B., Kirsner, R. S., & Jozic, I. (2021). Diabetic Wound-Healing Science. Medicina, 57(10), 1072. https://doi.org/10.3390/medicina57101072
Caturano, A., D’Angelo, M., Mormone, A., Russo, V., Mollica, M. P., Salvatore, T., Galiero, R., Rinaldi, L., Vetrano, E., Marfella, R., Monda, M., Giordano, A., & Sasso, F. C. (2023). Oxidative Stress in Type 2 Diabetes: Impacts from Pathogenesis to Lifestyle Modifications. Current Issues in Molecular Biology, 45(8), 6651–6666. https://doi.org/10.3390/cimb45080420
Deng, H., Li, B., Shen, Q., Zhang, C., Kuang, L., Chen, R., Wang, S., Ma, Z., & Li, G. (2023). Mechanisms of diabetic foot ulceration: A review. Journal of Diabetes, 15(4), 299–312. https://doi.org/10.1111/1753-0407.13372
Doğruel, H., Aydemir, M., & Balci, M. K. (2022). Management of diabetic foot ulcers and the challenging points: An endocrine view. World Journal of Diabetes, 13(1), 27–36. https://doi.org/10.4239/wjd.v13.i1.27
Ead, J. K., & Armstrong, D. G. (2023). Granulocyte-macrophage colony-stimulating factor: Conductor of the wound healing orchestra? International Wound Journal, 20(4), 1229–1234. https://doi.org/10.1111/iwj.13919
Everett, E., & Mathioudakis, N. (2018). Update on management of diabetic foot ulcers. Annals of the New York Academy of Sciences, 1411(1), 153–165. https://doi.org/10.1111/nyas.13569
Fang, Y., Gong, S. J., Xu, Y. H., Hambly, B. D., & Bao, S. (2007). Impaired cutaneous wound healing in granulocyte/macrophage colony-stimulating factor knockout mice. British Journal of Dermatology, 157(3), 458–465. https://doi.org/10.1111/j.1365-2133.2007.07979.x
Farooq, M., Khan, A. W., Kim, M. S., & Choi, S. (2021). The Role of Fibroblast Growth Factor (FGF) Signaling in Tissue Repair and Regeneration. Cells, 10(11), 3242.
https://doi.org/10.3390/cells10113242
Galicia-Garcia, U., Benito-Vicente, A., Jebari, S., Larrea-Sebal, A., Siddiqi, H., Uribe, K. B., Ostolaza, H., & Martín, C. (2020). Pathophysiology of Type 2 Diabetes Mellitus. International Journal of Molecular Sciences, 21(17). https://doi.org/10.3390/ijms21176275
Galkowska, H., Wojewodzka, U., & Olszewski, W. L. (2006). Chemokines, cytokines, and growth factors in keratinocytes and dermal endothelial cells in the margin of chronic diabetic foot ulcers. Wound Repair and Regeneration : Official Publication of the Wound Healing Society [and] the European Tissue Repair Society, 14(5), 558–565. https://doi.org/10.1111/j.1743- 6109.2006.00155.x
Gonçalves, R. V., Freitas, M. B., & Esposito, D. (2022). Cellular and Molecular Mechanisms of Oxidative Stress in Wound Healing. Oxidative Medicine and Cellular Longevity, 2022, 1–2. https://doi.org/10.1155/2022/9785094
Guo, H., Wu, H., & Li, Z. (2023). The Pathogenesis of Diabetes. International Journal of Molecular Sciences, 24(8), 6978. https://doi.org/10.3390/ijms24086978
Hossain, Md. J., Al‐Mamun, Md., & Islam, Md. R. (2024). Diabetes mellitus, the fastest growing global public health concern: Early detection should be focused. Health Science Reports, 7(3). https://doi.org/10.1002/hsr2.2004
Kaur, M., Misra, S., Swarnkar, P., Patel, P., Das Kurmi, B., Das Gupta, G., & Singh, A. (2023). Understanding the role of hyperglycemia and the molecular mechanism associated with diabetic neuropathy and possible therapeutic strategies. Biochemical Pharmacology, 215, 115723. https://doi.org/10.1016/j.bcp.2023.115723
Khalid, M., Petroianu, G., & Adem, A. (2022). Advanced Glycation End Products and Diabetes Mellitus: Mechanisms and Perspectives. Biomolecules, 12(4), 542. https://doi.org/10.3390/biom12040542
Kim, J., Nomkhondorj, O., An, C. Y., Choi, Y. C., & Cho, J. (2023). Management of diabetic foot ulcers: a narrative review. Journal of Yeungnam Medical Science, 40(4), 335–342. https://doi.org/10.12701/jyms.2023.00682
Lazarus, H. M., Pitts, K., Wang, T., Lee, E., Buchbinder, E., Dougan, M., Armstrong, D. G., Paine, R., Ragsdale, C. E., Boyd, T., Rock, E. P., & Gale, R. P. (2022). Recombinant GM-CSF for diseases of GM-CSF insufficiency: Correcting dysfunctional mononuclear phagocyte disorders. Frontiers in Immunology, 13, 1069444 https://doi.org/10.3389/fimmu.2022.1069444
Liu, Y., Liu, D., Guo, G., Mao, Y., & Wang, X. (2014). [Effects of recombinant human granulocyte-macrophage colony-stimulating factor on wound healing and microRNA expression in diabetic rats]. Zhonghua Shao Shang Za Zhi = Zhonghua Shaoshang Zazhi = Chinese Journal of Burns, 30(3), 243–250.
Mann, A., Breuhahn, K., Schirmacher, P., & Blessing, M. (2001). Keratinocyte-derived granulocyte-macrophage colony stimulating factor accelerates wound healing: Stimulation of keratinocyte proliferation, granulation tissue formation, and vascularization. Journal of Investigative Dermatology, 117(6), 1382–1390. https://doi.org/10.1046/j.0022- 202x.2001.01600.x
Mieczkowski, M., Mrozikiewicz-Rakowska, B., Kowara, M., Kleibert, M., & Czupryniak, L. (2022). The Problem of Wound Healing in Diabetes—From Molecular Pathways to the Design of an Animal Model. International Journal of Molecular Sciences, 23(14), 7930. https://doi.org/10.3390/ijms23147930
Naim, Z., Supit, L., Sutrisno, E., & Buchari, F. B. (1970). Granulocyte-Macrophage Colony Stimulating Factor and Steroid on Neovascularization and Keratinocyte Proliferation in Wound Healing. Jurnal Plastik Rekonstruksi, 1(2), 5–7. https://doi.org/10.14228/jpr.v1i2.55
Oliver, T. I., & Mutluoglu, M. (2023). Diabetic Foot Ulcer. In StatPearls.
Polaka, S., Katare, P., Pawar, B., Vasdev, N., Gupta, T., Rajpoot, K., Sengupta, P., & Tekade, R.
K. (2022). Emerging ROS-Modulating Technologies for Augmentation of the Wound Healing Process. ACS Omega, 7(35), 30657–30672. https://doi.org/10.1021/acsomega.2c02675
Raja, J. M., Maturana, M. A., Kayali, S., Khouzam, A., & Efeovbokhan, N. (2023). Diabetic foot ulcer: A comprehensive review of pathophysiology and management modalities. World Journal of Clinical Cases, 11(8), 1684–1693. https://doi.org/10.12998/wjcc.v11.i8.1684
Ramirez-Acuña, J. M., Cardenas-Cadena, S. A., Marquez-Salas, P. A., Garza-Veloz, I., Perez- Favila, A., Cid-Baez, M. A., Flores-Morales, V., & Martinez-Fierro, M. L. (2019). Diabetic Foot Ulcers: Current Advances in Antimicrobial Therapies and Emerging Treatments. Antibiotics, 8(4), 193. https://doi.org/10.3390/antibiotics8040193
Raziyeva, K., Kim, Y., Zharkinbekov, Z., Kassymbek, K., Jimi, S., & Saparov, A. (2021). Immunology of Acute and Chronic Wound Healing. Biomolecules, 11(5), 700. https://doi.org/10.3390/biom11050700
Sapra, A., & Bhandari, P. (2023). Diabetes. StatPearls. https://www.ncbi.nlm.nih.gov/books/NBK551501/
Sawaya, A. P., Stone, R. C., Brooks, S. R., Pastar, I., Jozic, I., Hasneen, K., O’Neill, K., Mehdizadeh, S., Head, C. R., Strbo, N., Morasso, M. I., & Tomic-Canic, M. (2020). Deregulated immune cell recruitment orchestrated by FOXM1 impairs human diabetic wound healing. Nature Communications, 11(1), 4678. https://doi.org/10.1038/s41467-020-18276-0
Shiomi, A., & Usui, T. (2015). Pivotal Roles of GM‐CSF in Autoimmunity and Inflammation.
Mediators of Inflammation, 2015(1). https://doi.org/10.1155/2015/568543
Wang, X., Yuan, C.-X., Xu, B., & Yu, Z. (2022). Diabetic foot ulcers: Classification, risk factors and management. World Journal of Diabetes, 13(12), 1049–1065. https://doi.org/10.4239/wjd.v13.i12.1049
Wessendarp, M., Watanabe-Chailland, M., Liu, S., Stankiewicz, T., Ma, Y., Kasam, R. K., Shima, K., Chalk, C., Carey, B., Rosendale, L.-R., Dominique Filippi, M., & Arumugam, P. (2022). Role of GM-CSF in regulating metabolism and mitochondrial functions critical to macrophage proliferation. Mitochondrion, 62, 85–101. https://doi.org/10.1016/j.mito.2021.10.009
Yan, H., Chen, J., & Peng, X. (2012). Recombinant human granulocyte-macrophage colony- stimulating factor hydrogel promotes healing of deep partial thickness burn wounds. Burns, 38(6), 877–881. https://doi.org/10.1016/j.burns.2012.02.001
Yuan, L., Minghua, C., Feifei, D., Runxiu, W., Ziqiang, L., Chengyue, M., & Wenbo, J. (2015). Study of the use of recombinant human granulocyte-macrophage colony-stimulating factor hydrogel externally to treat residual wounds of extensive deep partial-thickness burn. Burns, 41(5), 1086–1091. https://doi.org/10.1016/j.burns.2014.12.004
Zhang, X., Tao, J., Gong, S., Yu, X., & Shao, S. (2024). Effects of Recombinant Human Granulocyte/Macrophage Colony-Stimulating Factor on Diabetic Lower Extremity Ulcers: Case Series of Nine Patients. Diabetes, Metabolic Syndrome and Obesity, Volume 17, 1941– 1956. https://doi.org/10.2147/DMSO.S461349
Zhao, R., Liang, H., Clarke, E., Jackson, C., & Xue, M. (2016). Inflammation in Chronic Wounds.
International Journal of Molecular Sciences, 17(12), 2085. https://doi.org/10.3390/ijms17122085
Cruciani, M., Lipsky, B. A., Mengoli, C., & de Lalla, F. (2013). Granulocyte-colony stimulating factors as adjunctive therapy for diabetic foot infections. Cochrane Database of Systematic Reviews, 2013(8), CD006810.
Zhang, X., Tao, J., Gong, S., Yu, X., & Shao, S. (2024). Effects of recombinant human granulocyte/macrophage colony-stimulating factor on diabetic lower extremity ulcers: Case series of nine patients [Response to Letter]. Diabetes, Metabolic Syndrome and Obesity, 17, 2201–2202.
Kinali, H., Kalaycioglu, G. D., Boyacioglu, O., Korkusuz, P., Aydogan, N., & Vargel, I. (2024). Clinic-oriented injectable smart material for the treatment of diabetic wounds: Coordinating the release of GM-CSF and VEGF. International Journal of Biological Macromolecules, 276(Part 1).
Copyright (c) 2025 Indonesian Journal of Global Health Research
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
