To verify the influence of ozone (O3) therapy on an experimental model of rheumatoid arthritis (RA), 30 male Wistar rats were randomly allocated to 2 groups, control (C) and treatment (T), and subdivided into control (C12, C48, C72) and treatment (T12, T48, T72) groups. RA was induced by administration of collagenase plus complete Freud’s adjuvant in the knee joint region. The animals were treated with ozone therapy (1 ml O3 injection in the knee i.a.) according to group assignment: T12, 2 h; T48, 2 and 24 h; and T72, 2, 24, and 48 h post-RA induction. The different animal groups were euthanized 12, 24, or 72 h post-RA induction, respectively. Synovial exudate levels of IL-10, IL-12p70, TNF-α, INF-γ, and MCP-1 were assessed by flow cytometry, and histopathological analysis of the knee cartilage was conducted. Ozone therapy effectively decreases inflammation, reducing IL-12 and TNF-α, and increasing IL10. O3 did not statistically affect INF-γ or MCP-1 levels. More expressive results were obtained with group T72, i.e., treated 2, 24, and 48 h post-RA induction, which indicates that longer-term ozone treatment is more effective than a single acute application. Ozone therapy effectively reduced inflammation with effects, at least in part, mediated through reduction of pro-inflammatory cytokines and activation of IL-10 anti-inflammatory cytokine.
This is a preview of subscription content, access via your institution.
Buy single article
Instant access to the full article PDF.
Tax calculation will be finalised during checkout.
Tedgui, A., and Z. Mallat. 2001. Anti-inflammatory mechanisms in the vascular wall. Circulation Research 88: 877–887. https://doi.org/10.1161/hh0901.090440.
Ham, S., J.B. Bae, S. Lee, B.J. Kim, B.G. Han, S.K. Kwok, and T. Young Roh. 2019. Epigenetic analysis in rheumatoid arthritis synoviocytes. In Experimental and Molecular Medicine 51, vol. 51, 1–13. Springer: US. https://doi.org/10.1038/s12276-019-0215-5.
Kapoor, T., and J. Bathon. 2018. Renal manifestations of rheumatoid arthritis. Rheumatic Disease Clinics of North America 44. Elsevier Inc: 571–584. https://doi.org/10.1016/j.rdc.2018.06.008.
Chin, C.Y., S.Y. Hsieh, and V.S. Tseng. 2018. EDram: effective early disease risk assessment with matrix factorization on a large-scale medical database: a case study on rheumatoid arthritis. PLoS One 13: 1–19. https://doi.org/10.1371/journal.pone.0207579.
Hammer, Hilde, B. Berner, S. Michelsen, A. Provan, J. Sexton, J. Lampa, T. Uhlig, and T.K. Kvien. 2018. Tender joint count may not reflect inflammatory activity in established rheumatoid arthritis patients - results from a longitudinal study. Arthritis Care and Research. https://doi.org/10.1002/acr.23815.
León, Fernández, O. Sonia, R. Viebahn-Haensler, G.L. Cabreja, I.S. Espinosa, Y.H. Matos, L.D. Roche, B.T. Santos, G.T. Oru, and J.C.P. Vega. 2016. Medical ozone increases methotrexate clinical response and improves cellular redox balance in patients with rheumatoid arthritis. European Journal of Pharmacology 789. Elsevier: 313–318. https://doi.org/10.1016/j.ejphar.2016.07.031.
Vaillant, Jaqueline, Dranguet, A. Fraga, M.T. Díaz, A. Mallok, R. Viebahn-Hänsler, Z. Fahmy, A. Barberá, L. Delgado, S. Menéndez, and O.S.L. Fernández. 2013. Ozone oxidative postconditioning ameliorates joint damage and decreases pro-inflammatory cytokine levels and oxidative stress in PG/PS-induced arthritis in rats. European Journal of Pharmacology 714. Elsevier: 318–324. https://doi.org/10.1016/j.ejphar.2013.07.034.
Hammond, Alison. 2004. Rehabilitation in rheumatoid arthritis: a critical review. Musculoskeletal Care 2: 135–151. https://doi.org/10.1002/msc.66.
Katz, Jeffrey. 2006. Lumbar disc disorders and low-back pain: socioeconomic factors and consequences. Journal of Bone and Joint Surgery - Series A 88: 21–24. https://doi.org/10.2106/JBJS.E.01273.
Kallewaard, J.W., M. Terheggen, G.J. Groen, M.E. Sluijter, R. Derby, L. Kapural, N. Mekhail, and M. van Kleef. 2010. Evidence-based interventional pain medicine. 15. Discogenic low back pain. Pain Practice 10: 560–579. https://doi.org/10.1111/j.1533-2500.2010.00408.x.
Pereira, Marcelo Monteiro Sad, A. Navarini, L.M.J. Mimica, A.M. Pacheco Jr., and R.A. Silva. 2005. Efeito de diferentes gases sobre o crescimento bacteriano: estudo experimental “in vitro”. Revista do Colégio Brasileiro de Cirurgiões 32: 12–14. https://doi.org/10.1590/s0100-69912005000100004.
Tirelli, U., C. Cirrito, M. Pavanello, C. Piasentin, A. Lleshi, and R. Taibi. 2019. Ozone therapy in 65 patients with fibromyalgia: an effective therapy. European Review for Medical and Pharmacological Sciences 23: 1786–1788. https://doi.org/10.26355/eurrev_201902_17141.
Smith, Noel, A. Wilson, J. Gandhi, S. Vatsia, and S. Khan. 2017. Ozone therapy: an overview of pharmacodynamics, current research, and clinical utility. Medical Gas Research 7: 212–219. https://doi.org/10.4103/2045-9912.215752.
Felder-Puig, Rosemarie, M. Gyimesi, T. Mittermayr, and S. Geiger-Gritsch. 2009. Chemonukleolyse und intradiskale Elektrotherapie: Was Ist die gegenwärtige Evidenz? RoFo Fortschritte auf dem Gebiet der Rontgenstrahlen und der Bildgebenden Verfahren 181: 936–944. https://doi.org/10.1055/s-0028-1109573.
Di Mauro, Rosaria, G. Cantarella, R. Bernardini, M. Di Rosa, I. Barbagallo, A. Distefano, L. Longhitano, et al. 2019. The biochemical and pharmacological properties of ozone: the smell of protection in acute and chronic diseases. International Journal of Molecular Sciences 20. https://doi.org/10.3390/ijms20030634.
Manoto, Sello, M.J. Maepa Lebohang, and S.K. Motaung. 2018. Medical ozone therapy as a potential treatment modality for regeneration of damaged articular cartilage in osteoarthritis. Saudi Journal of Biological Sciences 25. King Saud University: 672–679. https://doi.org/10.1016/j.sjbs.2016.02.002.
Braidy, Nady, Izadi Morteza, A. Sureda, N. Jonaidi-Jafari, A. Banki, S.F. Nabavi, and M.N. Seyed. 2018. Therapeutic relevance of ozone therapy in degenerative diseases: focus on diabetes and spinal pain. Journal of Cellular Physiology 233: 2705–2714. https://doi.org/10.1002/jcp.26044.
Marcelo, Freire, and T.E.V. Dyke. 2013. Natural resolution of inflammation. Periodontology 2000 (63): 149–164.
Aisha, Siddiqah, J. Ahmed, H. Li, A. Stark Erlandsson-Harris, and G.B.M. Ahmede. 2012. Suppression of pain and joint destruction by inhibition of the proteasome system in experimental osteoarthritis. Pain 153 (1): 18–26.
Combe, R., S. Bramwell, and M.J. Field. 2004. The monosodium iodoacetate model of osteoarthritis: a model of chronic nociceptive pain in rats? Neuroscience Letters 370 (2–3): 236–240.
Bove, S.E., S.L. Calcaterra, R.M. Brooker, C.M. Huber, R.E. Guzman, P.L. Juneau, D.J. Schrier, and K.S. Kilgore. 2003. Weight bearing as a measure of disease progression and efficacy of anti-inflammatory compounds in a model of monosodium iodoacetate-induced osteoarthritis. Osteoarthritis and Cartilage 11 (11): 821–830.
Pitcher, T., J. Sousa-Valente, and M. Malcangio. 2016. The monoiodoacetate model of osteoarthritis pain in the mouse. Journal of Visualized Experiments 111: e53746. https://doi.org/10.3791/53746.
Chen, Huiqiang, B. Yu, C. Lu, and Q. Lin. 2013. The effect of intra-articular injection of different concentrations of ozone on the level of TNF-α, TNF-R1, and TNF-R2 in rats with rheumatoid arthritis. Rheumatology International 33: 1223–1227. https://doi.org/10.1007/s00296-012-2529-7.
Liou, Lieh Bang, W.P. Tsai, C.J. Chang, W. Ju Chao, and M. Hsin Chen. 2013. Blood monocyte chemotactic protein-1 (MCP-1) and adapted disease activity Score28-MCP-1: favorable indicators for rheumatoid arthritis activity. PLoS One 8: 1–9. https://doi.org/10.1371/journal.pone.0055346.
Rajaiah, Rajesh, M. Puttabyatappa, S.K. Polumuri, and K.D. Moudgil. 2011. Interleukin-27 and interferon-γ are involved in regulation of autoimmune arthritis. Journal of Biological Chemistry 286: 2817–2825. https://doi.org/10.1074/jbc.M110.187013.
Trinchieri, Giorgio. 2003. Interleukin-12 and the regulation of innate resistance and adaptive immunity. Nature Reviews Immunology 3: 133–146. https://doi.org/10.1038/nri1001.
Noori-Zadeh, Ali, S. Bakhtiyari, R. Khooz, K. Haghani, and S. Darabi. 2019. Intra-articular ozone therapy efficiently attenuates pain in knee osteoarthritic subjects: a systematic review and meta-analysis. Complementary Therapies in Medicine 42. Elsevier: 240–247. https://doi.org/10.1016/j.ctim.2018.11.023.
Arias-Vázquez, Pedro Iván, C.A. Tovilla-Zárate, Y. Hernández-Díaz, T.B. González-Castro, I.E. Juárez-Rojop, M.L. López-Narváez, D.Y. Bermudez-Ocaña, H.A. Barjau-Madrígal, and G. Legorreta-Ramírez. 2019. Short-term therapeutic effects of ozone in the management of pain in knee osteoarthritis: a meta-analysis. PM & R : The Journal of Injury, Function, and Rehabilitation. https://doi.org/10.1002/pmrj.12088.
Conflict of Interest
The authors declare that they have no conflict of interest.
Human and Animal Rights
All procedures performed in animal studies were in accordance with the ethical standards of the institution or practice in which the studies were conducted. Ethics committee in research, CEUA, 037/2016.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
Cite this article
Tartari, A.P.S., Moreira, F.F., Pereira, M.C.D.S. et al. Anti-inflammatory Effect of Ozone Therapy in an Experimental Model of Rheumatoid Arthritis. Inflammation 43, 985–993 (2020). https://doi.org/10.1007/s10753-020-01184-2
- ozone therapy