Ozone Therapy: A Critical Physiological and Diverse Clinical Evaluation with Regard to Immune Modulation, Anti-Infectious Properties, Anti-Cancer Potential, and Impact on Anti-Oxidant Enzymes

DOI: 10.4236/ojmip.2015.53004   PDF   HTML   XML   4,866 Downloads   7,009 Views   Citations


Ozone therapy has been marred by conventional science for years due to many flawed experimental designs or small sample sizes of the population in which it intends to study. For this reason, many physicians have dismissed ozone therapy and limited funds have been delegated to furthering the knowledge of its therapeutic effects. However, there is evidence that suggests that ozone does have various therapeutic effects that range from disinfection of pathogens, anticancer properties, and treatment of back ailments. In this paper, we have collected the more promising studies that suggest the efficacy and safety of ozone therapy primarily focusing on autohemotherapy. This paper is designed to promote awareness of ozone therapy and to show some supporting evidence of its efficacy. Clinically, ozone therapy is often used adjunctively and combined with other treatment modalities to enhance or encourage a desired mechanism of action. Since the efficacy of ozone alone is still contentious, it is important to note that ozone therapy should be used in conjunction with other various treatments with very few exceptions.

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J. Smith, A. , Oertle, J. , Warren, D. and Prato, D. (2015) Ozone Therapy: A Critical Physiological and Diverse Clinical Evaluation with Regard to Immune Modulation, Anti-Infectious Properties, Anti-Cancer Potential, and Impact on Anti-Oxidant Enzymes. Open Journal of Molecular and Integrative Physiology, 5, 37-48. doi: 10.4236/ojmip.2015.53004.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] Wolff, H.H. (1974) Die Behandlung peripherer Durchblutungsstörungen mit Ozon. Erfahr. Hk, 23, e181-e184.
[2] Bocci, V.A. (2006) Scientific and Medical Aspects of Ozone Therapy. State of the Art. Archives of Medical Research, 37, 425-435.
[3] Babior, B.M. (1978) Oxygen-Dependent Microbial Killing by Phagocytes. New England Journal of Medicine, 298, 659-668.
[4] Babior, B.M. (1978) Oxygen-Dependent Microbial Killing by Phagocytes. New England Journal of Medicine, 298, 721-725.
[5] Fialkow, L., Wang, Y. and Downey, G.P. (2007) Reactive Oxygen and Nitrogen Species as Signaling Molecules Regulating Neutrophil Function. Free Radical Biology and Medicine, 42, 153-164.
[6] Sweet, F., Kao, M.S., Lee, S.C., Hagar, W.L. and Sweet, W.E. (1980) Ozone Selectively Inhibits Growth of Human Cancer Cells. Science, 209, 931-933.
[7] Tarkington, B.K., Duvall, T.R. and Last, J.A. (1994) Ozone Exposure of Cultured Cells and Tissues. Methods in Enzymology, 234, 257-265.
[8] Larini, A., Bianchi, L. and Bocci, V. (2003) The Ozone Tolerance: (I) Enhancement of Antioxidant Enzymes Is Ozone Dose-Dependent in Jurkat Cells. Free Radical Research, 37, 1163-1168.
[9] Leist, M., Raab, B., Maurer, S. and Brigelius-Flohé, R. (1996) Conventional Cell Culture Media Do Not Adequately Supply Cells with Antioxidants and thus Facilitate Peroxide-Induced Genotoxicity. Free Radical Biology and Medicine, 21, 297-306.
[10] Halliwell, B. (1996) Antioxidants in Human Health and Disease. Annual Review of Nutrition, 16, 33-50.
[11] Halliwell, B. (1999) Antioxidant Defense Mechanisms: From the Beginning to the End (of the Beginning). Free Radical Research, 31, 261-272.
[12] Halliwell, B. (2003) Oxidative Stress in Cell Culture: An Under-Appreciated Problem? FEBS Letters, 540, 3-6.
[13] Larini, A., Bianchi, L. and Bocci, V. (2004) Effect of 4-Hydroxynonenal on Antioxidant Capacity and Apoptosis Induction in Jurkat T Cells. Free Radical Research, 38, 509-516.
[14] Bocci, V., Borrelli, E., Travagli, V. and Zanardi, I. (2009) The Ozone Paradox: Ozone Is a Strong Oxidant as Well as a Medical Drug. Medicinal Research Reviews, 29, 646-682.
[15] Halliwell, B., Clement, M.V. and Long, L.H. (2000) Hydrogen Peroxide in the Human Body. FEBS Letters, 486, 10-13.
[16] Halliwell, B., Clement, M.V., Ramalingam, J. and Long, L.H. (2000) Hydrogen Peroxide: Ubiquitous in Cell Culture and in Vivo? IUBMB Life, 50, 251-257.
[17] Antunes, F. and Cadenas, E. (2000) Estimation of H2O2 Gradients across Biomembranes. FEBS Letters, 475, 121-126.
[18] Bocci, V., Aldinucci, C. and Bianchi, L. (2005) The Use of Hydrogen Peroxide as Medical Drug. Rivista Italiana di Ossigeno-Ozonoterapia, 4, 30-39.
[19] Stone, J.R. and Yang, S. (2006) Hydrogen Peroxide: A Signaling Messenger. Antioxidants & Redox Signaling, 8, 243-270.
[20] Forman, H.J. (2008) Hydrogen Peroxide: The Good, the Bad and the Ugly. In: Valacchi, G. and Davis, P., Eds., Oxidants in Biology, Springer, Dordrecht, 1-17.
[21] Baeuerle, P.A. and Henkel, T. (1994) Function and Activation of NF-Kappa B in the Immune System. Annual Review of Immunology, 12, 141-179.
[22] Los, M., Droge, W., Stricker, K., Baeuerle, P.A. and Schulze-Osthoff, K. (1995) Hydrogen Peroxide as a Potent Activator of T Lymphocyte Functions. European Journal of Immunology, 25, 159-165.
[23] Stone, J.R. and Collins, T. (2002) The Role of Hydrogen Peroxide in Endothelial Proliferative Responses. Endothelium, 9, 231-238.
[24] Grisham, M.B. (2004) Reactive Oxygen Species in Immune Responses. Free Radical Biology and Medicine, 36, 1479-1480.
[25] Ardanaz, N. and Pagano, P.J. (2006) Hydrogen Peroxide as a Paracrine Vascular Mediator: Regulation and Signaling Leading to Dysfunction. Experimental Biology and Medicine, 231, 237-251.
[26] Urschel, H.C. (1967) Cardiovascular Effects of Hydrogen Peroxide: Current Status. Diseases of the Chest, 51, 180-192.
[27] Lacy, F., O’Connor, D.T. and Schmid-Schonbein, G.W. (1998) Plasma Hydrogen Peroxide Production in Hypertensives and Normotensive Subjects at Genetic Risk of Hypertension. Journal of Hypertension, 16, 291-303.
[28] Travagil, V., Zanardi, I., Bernini, P., Nepi, S., Tenori, L. and Bocci, V. (2010) Effects of Ozone Blood Treatment on the Metabolite Profile of Human Blood. International Journal of Toxicology, 29, 165-174.
[29] Miller, D.B., Karoly, E.D., Jones, J.C., Ward, W.O., Vallanat, B.D., et al. (2015) Inhaled Ozone (O3)-Induces Changes in Serum Metabolomics and Liver Transcriptomic Profiles in Rats. Toxicology and Applied Pharmacology, 286, 65-79.
[30] Mohanty, J.G., Nagababu, E. and Rifkind, J.M. (2014) Red Blood Cell Oxidative Stress Impairs Oxygen Delivery and Induces Red Blood Cell Aging. Frontiers in Physiology, 5, 1-6.
[31] Callsen, D., Sandau, K.B. and Brune, B. (1999) Nitric Oxide and Superoxide Inhibit Platelet-Derived Growth Factor Receptor Phosphotyrosine Phosphatases. Free Radical Biology and Medicine, 26, 1544-1553.
[32] Sundaresan, M., Yu, Z.X., Ferrans, V.J., Irani, K. and Finkel, T. (1995) Requirement for Generation of H2O2 for Platelet-Derived Growth Factor Signal Transduction. Science, 270, 296-299.
[33] Valacchi, G. and Bocci, V. (2000) Studies on the Biological Effects of Ozone: 11. Release of Factors from Human Endothelial Cell. Mediators of Inflammation, 9, 271-276.
[34] Paulesu, L., Luzzi, E. and Bocci, V. (1991) Studies on the Biological Effects of Ozone: 2. Induction of Tumor Necrosis Factor (TNF-Alpha) on Human Leucocytes. Lymphokine and Cytokine Research, 10, 409-412.
[35] Bocci, V., Luzzi, E., Corradeschi, F., Paulesu, L. and Di Stefano, A. (1993) Studies on the Biological Effects of Ozone: 3. An Attempt to Define Conditions for Optimal Induction of Cytokines. Lymphokine and Cytokine Research, 12, 121- 126.
[36] Bocci, V., Luzzi, E., Corradeschi, F. and Paulesu, L. (1994) Studies on the Biological Effects of Ozone: 5. Evaluation of Immunological Parameters and Tolerability in Normal Volunteers Receiving Ambulatory Autohaemotherapy. Biotherapy, 7, 83-90.
[37] Bocci, V., Valacchi, G., Corradeschi, F. and Fanetti, G. (1998) Studies on the Biological Effects of Ozone: 8. Effects on the Total Antioxidant Status and on Interleukin-8 Production. Mediators of Inflammation, 7, 331-337.
[38] Steppan, J., Meaders, T., Muto, M. and Murphy, K. (2010) A Mettaanalysis of the Effectiveness and Safety of Ozone Treatments for Herniated Lumbar Discs. Journal of Vascular and Interventional Radiology, 21, 534-548.
[39] Rilling, S. and Viebahn, R. (1987) The Use of Ozone in Medicine. 2nd Edition, Karl F. Haug Publisher, Heidelberg, 7-187.
[40] Rokitansky, O., Rokitansky, A., Steiner, J., et al. (1981) Ozontherapie bei peripheren, arteriellen. In: Wasser, I.O.A., Ed., Durchblutungsstorungen: Klinik, biochemisheund blutgasanalytische untersuchungen, Ozon-Weltkongress, Berlin, 53-75.
[41] Bocci, V. (1994) Autohaemotherapy after Treatment of Blood with Ozone: A Reappraisal. International Research Journals, 22, 131-144.
[42] Coppola, L., Verazzo, G., Giuta, R., et al. (1992) Oxygen-Ozone Therapy and Hemorrheological Parameters in Peripheral Chronic Arterial Occlusive Disease. Trombosi e Aterosclerosi, 3, 85-89.
[43] Iliakis, E., Valadakis, V., Vynios, D.H., Tisiganos, C.P. and Agapitos, E. (2001) Rationalization of the Activity of Medical Ozone on Intervertebral Disc: A Histological and Biochemical Study. Rivista di Neuroradiologia, 14, 23-30.
[44] Bocci, V., Luzzi, E., Corradeschi, F., et al. (1993) Studies on the Biological Effects of Ozone: III, an Attempt to Define Conditions for Optimal Induction of Cytokines. Lymphokine and Cytokine Research, 12, 121-126.
[45] Brown, M.R., Miller Jr., F.J., Li, W.G., Ellingson, A.N., Mozena, J.D., Chatterjee, P., et al. (1999) Overexpression of Human Catalase Inhibits Proliferation and Promotes Apoptosis in Vascular Smooth Muscle Cells. Circulation Research, 85, 524-533.
[46] del Bello, D., Paolicchi, A., Comporti, M., Pompella, A. and Maellaro, E. (1999) Hydrogen Peroxide Produced during Gammaglutamyl Transpeptidase Activity Is Involved in Prevention of Apoptosis and Maintainance of Proliferation in U937 Cells. The FASEB Journal, 13, 69-79.
[47] Qian, Y., Luo, J., Leonard, S.S., Harris, G.K., Millecchia, L., Flynn, D.C. and Shi, X. (2003) Hydrogen Peroxide Formation and Actin Filament Reorganization by Cdc42 Are Essential for Ethanol-Induced in Vitro Angiogenesis. The Journal of Biological Chemistry, 278, 16189-16197.
[48] Arbiser, J.L., Petros, J., Klafter, R., Govindajaran, B., McLaughlin, E.R., Brown, L.F., et al. (2002) Reactive Oxygen Generated by Nox1 Triggers the Angiogenic Switch. Proceedings of the National Academy of Sciences of the United States of America, 99, 715-720.
[49] Burdon, R.H. (1995) Superoxide and Hydrogen Peroxide in Relation to Mammalian Cell Proliferation. Free Radical Biology and Medicine, 18, 775-794.
[50] Zanetti, M., Katusic, Z.S. and O’Brien, T. (2002) Adenoviral-Mediated Overexpression of Catalase Inhibits Endothelial Cell Proliferation. American Journal of Physiology—Heart and Circulatory Physiology, 283, H2620-H2626.
[51] Polytarchou, C., Hatziapostolou, M. and Papadimitriou, E. (2005) Hydrogen Peroxide Stimulates Proliferation and Migration of Human Prostate Cancer Cells through Activation of Activator Protein-1 and Up-Regulation of the Heparin Affin Regulatory Peptide Gene. Journal of Biological Chemistry, 280, 40428-40435.
[52] Ahmad, K.A., Iskandar, K.B., Hirpara, J.L., Clement, M.V. and Pervaiz, S. (2004) Hydrogen Peroxide-Mediated Cytosolic Acidification Is a Signal for Mitochondrial Translocation of Bax during Drug-Induced Apoptosis of Tumor Cells. Cancer Research, 64, 7867-7878.
[53] Hirpara, J.L., Clement, M.V. and Pervaiz, S. (2001) Intracellular Acidification Triggered by Mitochondrial-Derived Hydrogen Peroxide Is an Effector Mechanism for Drug-Induced Apoptosis in Tumor Cells. Journal of Biological Chemistry, 276, 514-521.
[54] Clement, M.V., Hirpara, J.L. and Pervaiz, S. (2003) Decrease in Intracellular Superoxide Sensitizes Bcl-2-Overexpressing Tumor Cells to Receptor and Drug-Induced Apoptosis Independent of the Mitochondria. Cell Death & Differentiation, 10, 1273-1285.
[55] Maeda, H., Hori, S., Ohizumi, H., Segawa, T., Kakehi, Y., Ogawa, O. and Kakizuka, A. (2004) Effective Treatment of Advanced Solid Tumors by the Combination of Arsenic Trioxide and L-Buthionine-Sulfoximine. Cell Death & Differentiation, 11, 737-746.
[56] Chen, Q., Espey, M.G., Krishna, M.C., Mitchell, J.B., Corpe, C.P., Buettner, G.R., et al. (2005) Pharmacologic Ascorbic Acid Concentrations Selectively Kill Cancer Cells: Action as a Pro-Drug to Deliver Hydrogen Peroxide to Tissues. Proceedings of the National Academy of Sciences of the United States of America, 102, 13604-13609.
[57] Djavaheri-Mergny, M., Wietzerbin, J. and Besancon, F. (2003) 2-Methoxyestradiol Induces Apoptosis in Ewing Sarcoma Cells through Mitochondrial Hydrogen Peroxide Production. Oncogene, 22, 2558-2567.
[58] Evens, A.M., Lecane, P., Magda, D., Prachand, S., Singhal, S., Nelson, J., Miller, R.A., et al. (2005) Motexafin Gadolinium Generates Reactive Oxygen Species and Induces Apoptosis in Sensitive and Highly Resistant Multiple Myeloma Cells. Blood, 105, 1265-1273.
[59] Diehn, M., et al. (2009) Association of Reactive Oxygen Species Levels and Radioresistance in Cancer Stem Cells. Nature, 458, 780-783.
[60] Sagal, M. and Bocci, V. (2011) Mechanisms of Action Involved in Ozone Therapy: Is Healing Induced via Mild Oxidative Stress? Medical Gas Research, 1, 1-18.
[61] Stoker, G. (1916) The Surgical Uses of Ozone. The Lancet, 188, 712.
[62] Travagli, V., Zanardi, I. and Bocci, V. (2009) Topical Applications of Ozone and Ozonated Oils as Anti-Infective Agents: An Insight into the Patent Claims. Recent Patents on Anti-Infective Drug Discovery, 4, 130-142.
[63] Travagli, V., Zanardi, I., Valacchi, G. and Bocci, V. (2010) Ozone and Ozonated Oils in Skin Diseases: A Review. Mediators of Inflammation, 2010, Article ID: 610418.
[64] Pryor, W.A. (1994) Mechanisms of Radical Formation from Reactions of Ozone with Target Molecules in the Lung. Free Radical Biology and Medicine, 17, 451-465.
[65] Sathishkumar, K., Haque, M., Perumal, T.E., et al. (2005) A Major Ozonation Product of Cholesterol, 3-Hydroxy- 5-oxo-5,6-secocholestan-6-al, Induces Apoptosis in H9c2 Cardiomyoblasts. FEBS Letters, 579, 6444-6450.
[66] Rösen, P., Nawroth, P.P. and King, G. (2001) The Role of Oxidative Stress in the Onset and Progression of Diabetes and Its Complications: A Summary of a Congress Series Sponsored by UNESCO-MCBN, the American Diabetes Association and the German Diabetes Society. Diabetes/Metabolism Research and Reviews, 17, 189-212.
[67] Al-Dalain, S.M., Martínez, G. and Candelario-Jalil, E. (2001) Ozone Treatment Reduces Markers of Oxidative and Endothelial Damage in an Experimental Diabetes Model in Rats. Pharmacological Research, 44, 391-396.
[68] Martínez-Sánchez, G., Al-Dalain, S.M., Menéndez, S., Re, L., Giuliani, A., Candelario-Jalil, E., Alvarez, H., Fernández-Montequín, J.I. and León, O.S. (2005) Therapeutic Efficacy of Ozone in Patients with Diabetic Foot. European Journal of Pharmacology, 523, 151-161.
[69] Rosales, F.A.H., Fernandez, J.L.C., Figueras, J.T., Cepero, S.M. and Perdomo, A.M. (2005) Ozone Therapy Effects on Biomarkers and Lung Function in Asthma. Archives of Medical Research, 36, 549-554.
[70] Bocci, V. (2002) Oxygen-Ozone Therapy. A Critical Evaluation. Kluwer Academic Publishers, Dordrecht.
[71] Ingram, M. and Barnes, E.M. (1954) Sterilization by Means of Ozone. Journal of Applied Microbiology, 17, 246-271.
[72] Burgassi, S., Zanardi, I., Travagli, V., Montomoli, E. and Bocci, V. (2009) How Much Ozone Bactericidal Activity Is Compromised by Plasma Components. Journal of Applied Microbiology, 106, 1715-1721.
[73] Nagayoshi, M., Fukuizumi, T., Kitamura, C., Yano, J., Terashita, M. and Nishihara, T. (2004) Efficacy of Ozone on Survival and Permeability of Oral Microorganisms. Oral Microbiology & Immunology, 19, 240-246.
[74] Oizumi, M., Suzuki, T., Uchida, M., Furuya, J. and Okamoto, Y. (1998) In Vitro Testing of a Denture Cleaning Method Using Ozone. Journal of Medical and Dental Sciences, 45, 135-139.
[75] Ebensberger, U., Pohl, Y. and Filippi, A. (2002) PCNA-Expression of Cementoblasts and Fibroblasts on the Root Surface after Extraoral Rinsing for Decontamination. Dental Traumatology, 18, 262-266.
[76] Huth, K.C., Jakob, F.M., Saugel, B., Cappello, C., Paschos, E., Hollweck, R., et al. (2006) Effect of Ozone on Oral Cells Compared with Established Antimicrobials. European Journal of Oral Sciences, 114, 435-440.
[77] Arita, M., Nagayoshi, M., Fukuizumi, T., Okinaga, T., Masumi, S., Morikawa, M., et al. (2005) Microbicidal Efficacy of Ozonated Water against Candida albicans Adhering to Acrylic Denture Plates. Oral Microbiology & Immunology, 20, 206-210.
[78] Murakami, H., Mizuguchi, M., Hattori, M., Ito, Y., Kawai, T. and Hasegawa, J. (2002) Effect of Denture Cleaner Using Ozone against Methicillin-Resistant Staphylococcus aureus and E. coli T1 Phage. Dental Materials Journal, 21, 53-60.
[79] Estrela, C., Estrela, C.R., Decurcio, D. de A., Silva, J.A. and Bammann, L.L. (2006) Antimicrobial Potential of Ozone in an Ultrasonic Cleaning System against Staphylococcus aureus. Brazilian Dental Journal, 17, 134-138.
[80] Suzuki, T., Oizumi, M., Furuya, J., Okamoto, Y. and Rosenstiel, S.F. (1999) Influence of Ozone on Oxidation of Dental Alloys. The International Journal of Prosthodontics, 12, 179-183.
[81] Nagayoshi, M., Kitamura, C., Fukuizumi, T., Nishihara, T. and Terashita, M. (2004) Antimicrobial Effect of Ozonated Water on Bacteria Invading Dentinal Tubules. Journal of Endodontics, 30, 778-781.
[82] Muller, P., Guggenheim, B. and Schmidlin, P.R. (2007) Efficacy of Gasiform Ozone and Photodynamic Therapy on a Multispecies Oral Biofilm in Vitro. European Journal of Oral Sciences, 115, 77-80.
[83] Estrela, C., Estrela, C.R.A., Decurcio, D.A., Hollanda, A.C.B. and Silva, J.A. (2007) Antimicrobial Efficacy of Ozonated Water, Gaseous Ozone, Sodium Hypochlorite and Chlorhexidine in Infected Human Root Canals. International Endodontic Journal, 40, 85-93.
[84] Hems, R.S., Gulabivala, K., Ng, Y.L., Ready, D. and Spratt, D.A. (2005) An in Vitro Evaluation of the Ability of Ozone to Kill a Strain of Enterococcus faecalis. International Endodontic Journal, 38, 22-29.

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