The Biochemical and Pharmacological Properties of Ozone: The Smell of Protection in Acute and Chronic Diseases

Rosaria Di Mauro, Giuseppina Cantarella, Renato Bernardini, Michelino Di Rosa, Ignazio Barbagallo, Alfio Distefano, Lucia Longhitano, Nunzio Vicario, Daniela Nicolosi, Giacomo Lazzarino, Daniele Tibullo, Maria Eugenia Gulino, Mariarita Spampinato, Roberto Avola, Giovanni Li Volti, Rosaria Di Mauro, Giuseppina Cantarella, Renato Bernardini, Michelino Di Rosa, Ignazio Barbagallo, Alfio Distefano, Lucia Longhitano, Nunzio Vicario, Daniela Nicolosi, Giacomo Lazzarino, Daniele Tibullo, Maria Eugenia Gulino, Mariarita Spampinato, Roberto Avola, Giovanni Li Volti

Abstract

Ozone therapy has been widely used in everyday clinical practice over the last few years, leading to significant clinical results in the treatment of herniated discs and pain management. Nevertheless, further studies have demonstrated its potential efficacy and safety under other clinical and experimental conditions. However, some of these studies showed controversial results regarding the safety and efficacy of ozone therapy, thus mining its potential use in an everyday clinical practice. To this regard, it should be considered that extensive literature review reported the use of ozone in a significant different dose range and with different delivery systems. The aim of the present review is to describe the various pharmacological effects of ozone in different organs and clinical conditions and to provide possible biochemical and molecular insights for ozone biological properties, thus providing a possible explanation for various controversial clinical outcomes described in the scientific literature.

Keywords: inflammation; medical gas; organ protection; oxidative stress; ozone.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The Gene Ontology analysis: (A) The dataset analysis showed that the 29 upregulated genes were involved in several immunological processes. The most significant process was Cell Chemotaxis (the negative Log of FDR (ngLogFDR) was 58, and the genes involved (GI) were 18). (B) The 309 downregulated genes identified during the GSE58682 analysis belong to the response to type I interferon (FDR = 14, GI = 16). Interestingly, the ability of antiviral response in subjects exposed to the ozone was significantly impaired.
Figure 2
Figure 2
The GeneMania network representation of the 29 upregulated and 309 downregulated genes: (A) The GO analysis of 29 genes involved during the exposition to a high ppb of ozone expresses (B) the cell chemotaxis and (C) inflammatory stimuli as biological processes. (D) The 309 downregulated genes in subjects exposed to a high ppb of ozone belong to the biological processes as a response to (E) the virus and to (F) Type I interferon.
Figure 3
Figure 3
High doses of ozone induce the gene transcription of the pro-inflammatory cytokine, its receptor, and inflammatory proteins. At the same time, we assist at a negative regulation of type 1 Interferon and the response to viral infections pathways.
Figure 4
Figure 4
A schematic representation of the possible mechanisms of action of ozone on the CNS.
Figure 5
Figure 5
A schematic representation of the possible mechanisms of action of ozone on skin diseases.
Figure 6
Figure 6
A schematic representation of the possible mechanisms of action of ozone in skin diseases.

References

    1. Dewar M.J. The structure of ozone. J. Chem. Soc. 1948;17:1299–1305. doi: 10.1039/jr9480001299.
    1. Cross C.E., Reznick A.Z., Packer L., Davis P.A., Suzuki Y.J., Halliwell B. Oxidative damage to human plasma proteins by ozone. Free Radic Res. Commun. 1992;15:347–352. doi: 10.3109/10715769209049150.
    1. Magalhaes F.N., Dotta L., Sasse A., Teixera M.J., Fonoff E.T. Ozone therapy as a treatment for low back pain secondary to herniated disc: A systematic review and meta-analysis of randomized controlled trials. Pain Physician. 2012;15:E115–E129.
    1. Smith N.L., Wilson A.L., Gandhi J., Vatsia S., Khan S.A. Ozone therapy: An overview of pharmacodynamics, current research, and clinical utility. Med. Gas. Res. 2017;7:212–219.
    1. Seyam O., Smith N.L., Reid I., Gandhi J., Jiang W., Khan S.A. Clinical utility of ozone therapy for musculoskeletal disorders. Med. Gas. Res. 2018;8:103–110.
    1. Kelly F.J., Mudway I., Krishna M.T., Holgate S.T. The free radical basis of air pollution: Focus on ozone. Respir. Med. 1995;89:647–656. doi: 10.1016/0954-6111(95)90131-0.
    1. Pryor W.A. Mechanisms of radical formation from reactions of ozone with target molecules in the lung. Free Radic Biol. Med. 1994;17:451–465. doi: 10.1016/0891-5849(94)90172-4.
    1. Leroy P., Tham A., Wong H., Tenney R., Chen C., Stiner R., Balmes J.R., Paquet A.C., Arjomandi M. Inflammatory and repair pathways induced in human bronchoalveolar lavage cells with ozone inhalation. PLoS ONE. 2015;10:e0127283. doi: 10.1371/journal.pone.0127283.
    1. Zuberi K., Franz M., Rodriguez H., Montojo J., Lopes C.T., Bader G.D., Morris Q. Genemania prediction server 2013 update. Nucleic Acids Res. 2013;41:W115–W122. doi: 10.1093/nar/gkt533.
    1. Chang J.T., Nevins J.R. Gather: A systems approach to interpreting genomic signatures. Bioinformatics. 2006;22:2926–2933. doi: 10.1093/bioinformatics/btl483.
    1. Mikerov A.N., Gan X., Umstead T.M., Miller L., Chinchilli V.M., Phelps D.S., Floros J. Sex differences in the impact of ozone on survival and alveolar macrophage function of mice after klebsiella pneumoniae infection. Respir. Res. 2008;9:24. doi: 10.1186/1465-9921-9-24.
    1. Paz C., Bazan-Perkins B. Sleep-wake disorganization in cats exposed to ozone. Neurosci. Lett. 1992;140:270–272. doi: 10.1016/0304-3940(92)90118-Q.
    1. Hackney J.D., Linn W.S., Buckley R.D., Pedersen E.E., Karuza S.K., Law D.C., Fischer A. Experimental studies on human health effects of air pollutants: I. Design considerations. Arch. Environ. Health. 1975;30:373–378. doi: 10.1080/00039896.1975.10666728.
    1. Rivas-Arancibia S., Vazquez-Sandoval R., Gonzalez-Kladiano D., Schneider-Rivas S., Lechuga-Guerrero A. Effects of ozone exposure in rats on memory and levels of brain and pulmonary superoxide dismutase. Environ. Res. 1998;76:33–39. doi: 10.1006/enrs.1997.3784.
    1. Guerrero A.L., Dorado-Martinez C., Rodriguez A., Pedroza-Rios K., Borgonio-Perez G., Rivas-Arancibia S. Effects of vitamin e on ozone-induced memory deficits and lipid peroxidation in rats. Neuroreport. 1999;10:1689–1692. doi: 10.1097/00001756-199906030-00012.
    1. Avila-Costa M.R., Colin-Barenque L., Fortoul T.I., Machado-Salas P., Espinosa-Villanueva J., Rugerio-Vargas C., Rivas-Arancibia S. Memory deterioration in an oxidative stress model and its correlation with cytological changes on rat hippocampus ca1. Neurosci. Lett. 1999;270:107–109. doi: 10.1016/S0304-3940(99)00458-9.
    1. Gackiere F., Saliba L., Baude A., Bosler O., Strube C. Ozone inhalation activates stress-responsive regions of the cns. J. Neurochem. 2011;117:961–972. doi: 10.1111/j.1471-4159.2011.07267.x.
    1. Mumaw C.L., Levesque S., McGraw C., Robertson S., Lucas S., Stafflinger J.E., Campen M.J., Hall P., Norenberg J.P., Anderson T., et al. Microglial priming through the lung-brain axis: The role of air pollution-induced circulating factors. FASEB J. 2016;30:1880–1891. doi: 10.1096/fj.201500047.
    1. Rowbotham G.F. A case of intractable pain in the head and face associated with pathological changes in the optic thalamus. Acta Neurochir. (Wien) 1960;9:1–8. doi: 10.1007/BF01809480.
    1. Bonica J.J. Pain-basic principles of management. Northwest Med. 1970;69:567–568.
    1. Hu B., Zheng J., Liu Q., Yang Y., Zhang Y. The effect and safety of ozone autohemotherapy combined with pharmacological therapy in postherpetic neuralgia. J. Pain Res. 2018;11:1637–1643. doi: 10.2147/JPR.S154154.
    1. Fuccio C., Luongo C., Capodanno P., Giordano C., Scafuro M.A., Siniscalco D., Lettieri B., Rossi F., Maione S., Berrino L. A single subcutaneous injection of ozone prevents allodynia and decreases the over-expression of pro-inflammatory caspases in the orbito-frontal cortex of neuropathic mice. Eur. J. Pharm. 2009;603:42–49. doi: 10.1016/j.ejphar.2008.11.060.
    1. Coppola L., Luongo C., Pastore A., Masciello C., Parascandola R.R., Mastrolorenzo L., Grassia A., Coppola A., De Biase M., Lettieri B., et al. Ozonized autohaemotransfusion could be a potential rapid-acting antidepressant medication in elderly patients. Int. J. Geriatr Psychiatry. 2010;25:208–213. doi: 10.1002/gps.2322.
    1. Frosini M., Contartese A., Zanardi I., Travagli V., Bocci V. Selective ozone concentrations may reduce the ischemic damage after a stroke. Free Radic. Res. 2012;46:612–618. doi: 10.3109/10715762.2012.659247.
    1. Salem N.A., Assaf N., Ismail M.F., Khadrawy Y.A., Samy M. Ozone therapy in ethidium bromide-induced demyelination in rats: Possible protective effect. Cell. Mol. Neurobiol. 2016;36:943–954. doi: 10.1007/s10571-015-0279-2.
    1. Zeng J., Lu J. Mechanisms of action involved in ozone-therapy in skin diseases. Int. Immunopharmacol. 2018;56:235–241. doi: 10.1016/j.intimp.2018.01.040.
    1. Burke K.E. Mechanisms of aging and development-a new understanding of environmental damage to the skin and prevention with topical antioxidants. Mech. Ageing Dev. 2018;172:123–130. doi: 10.1016/j.mad.2017.12.003.
    1. Shpektorova R.A. Ozone therapy of some skin diseases. Vestn. Derm. Venerol. 1964;38:44–46.
    1. Bialoszewski D., Kowalewski M. Superficially, longer, intermittent ozone theraphy in the treatment of the chronic, infected wounds. Ortop. Traumatol. Rehabil. 2003;5:652–658.
    1. Bocci V., Borrelli E., Valacchi G., Luzzi E. Quasi-total-body exposure to an oxygen-ozone mixture in a sauna cabin. Eur. J. Appl. Physiol. Occup. Physiol. 1999;80:549–554. doi: 10.1007/s004210050633.
    1. Bocci V. Biological and clinical effects of ozone. Has ozone therapy a future in medicine? Br. J. Biomed. Sci. 1999;56:270–279.
    1. Matsumoto K., Aizawa H., Inoue H., Koto H., Nakano H., Hara N. Role of neutrophil elastase in ozone-induced airway responses in guinea-pigs. Eur. Respir. J. 1999;14:1088–1094. doi: 10.1183/09031936.99.14510889.
    1. Jordan L., Beaver K., Foy S. Ozone treatment for radiotherapy skin reactions: Is there an evidence base for practice? Eur. J. Oncol. Nurs. 2002;6:220–227. doi: 10.1054/ejon.2002.0201.
    1. Kim H.S., Noh S.U., Han Y.W., Kim K.M., Kang H., Kim H.O., Park Y.M. Therapeutic effects of topical application of ozone on acute cutaneous wound healing. J. Korean Med. Sci. 2009;24:368–374. doi: 10.3346/jkms.2009.24.3.368.
    1. Al-Dalain S.M., Martinez G., Candelario-Jalil E., Menendez S., Re L., Giuliani A., Leon O.S. Ozone treatment reduces markers of oxidative and endothelial damage in an experimental diabetes model in rats. Pharm. Res. 2001;44:391–396. doi: 10.1006/phrs.2001.0867.
    1. Janic B., Umstead T.M., Phelps D.S., Floros J. Modulatory effects of ozone on thp-1 cells in response to sp-a stimulation. Am. J. Physiol. Lung. Cell. Mol. Physiol. 2005;288:L317–L325. doi: 10.1152/ajplung.00125.2004.
    1. Valacchi G., van der Vliet A., Schock B.C., Okamoto T., Obermuller-Jevic U., Cross C.E., Packer L. Ozone exposure activates oxidative stress responses in murine skin. Toxicology. 2002;179:163–170. doi: 10.1016/S0300-483X(02)00240-8.
    1. Kushmakov R., Gandhi J., Seyam O., Jiang W., Joshi G., Smith N.L., Khan S.A. Ozone therapy for diabetic foot. Med. Gas. Res. 2018;8:111–115.
    1. Valacchi G., Bocci V. Studies on the biological effects of ozone: 10. Release of factors from ozonated human platelets. Mediat. Inflamm. 1999;8:205–209. doi: 10.1080/09629359990360.
    1. Sen C.K., Khanna S., Babior B.M., Hunt T.K., Ellison E.C., Roy S. Oxidant-induced vascular endothelial growth factor expression in human keratinocytes and cutaneous wound healing. J. Biol. Chem. 2002;277:33284–33290. doi: 10.1074/jbc.M203391200.
    1. Krkl C., Yigit M.V., Ozercan I.H., Aygen E., Gulturk B., Artas G. The effect of ozonated olive oil on neovascularization in an experimental skin flap model. Adv. Ski. Wound Care. 2016;29:322–327. doi: 10.1097/01.ASW.0000484172.04260.46.
    1. Kesik V., Yuksel R., Yigit N., Saldir M., Karabacak E., Erdem G., Babacan O., Gulgun M., Korkmazer N., Bayrak Z. Ozone ameliorates doxorubicine-induced skin necrosis—Results from an animal model. Int. J. Low Extrem. Wounds. 2016;15:248–254. doi: 10.1177/1534734615597863.
    1. Guner M.H., Gorgulu T., Olgun A., Torun M., Kargi E. Effects of ozone gas on skin flaps viability in rats: An experimental study. J. Plast Surg. Hand Surg. 2016;50:291–297. doi: 10.3109/2000656X.2016.1170024.
    1. Roger V.L., Go A.S., Lloyd-Jones D.M., Adams R.J., Berry J.D., Brown T.M., Carnethon M.R., Dai S., de Simone G., Ford E.S., et al. Heart disease and stroke statistics--2011 update: A report from the american heart association. Circulation. 2011;123:e18–e209. doi: 10.1161/CIR.0b013e3182009701.
    1. Elahi M.M., Kong Y.X., Matata B.M. Oxidative stress as a mediator of cardiovascular disease. Oxidative Med. Cell. Longev. 2009;2:259–269. doi: 10.4161/oxim.2.5.9441.
    1. Ooi B.K., Goh B.H., Yap W.H. Oxidative stress in cardiovascular diseases: Involvement of nrf2 antioxidant redox signaling in macrophage foam cells formation. Int. J. Mol. Sci. 2017;18:2336. doi: 10.3390/ijms18112336.
    1. Rao V., Kiran R. Evaluation of correlation between oxidative stress and abnormal lipid profile in coronary artery disease. J. Cardiovasc. Dis. Res. 2011;2:57–60. doi: 10.4103/0975-3583.78598.
    1. Mason R.P. Optimal therapeutic strategy for treating patients with hypertension and atherosclerosis: Focus on olmesartan medoxomil. Vasc. Health Risk Manag. 2011;7:405–416. doi: 10.2147/VHRM.S20737.
    1. Bocci V., Travagli V., Zanardi I. May oxygen-ozone therapy improves cardiovascular disorders? Cardiovasc. Hematol. Disord. Drug Targets. 2009;9:78–85. doi: 10.2174/187152909788488681.
    1. Bayram H., Sapsford R.J., Abdelaziz M.M., Khair O.A. Effect of ozone and nitrogen dioxide on the release of proinflammatory mediators from bronchial epithelial cells of nonatopic nonasthmatic subjects and atopic asthmatic patients in vitro. J. Allergy Clin. Immunol. 2001;107:287–294. doi: 10.1067/mai.2001.111141.
    1. Bocci V.A., Zanardi I., Travagli V. Ozone acting on human blood yields a hormetic dose-response relationship. J. Transl. Med. 2011;9:66. doi: 10.1186/1479-5876-9-66.
    1. Pecorelli A., Bocci V., Acquaviva A., Belmonte G., Gardi C., Virgili F., Ciccoli L., Valacchi G. Nrf2 activation is involved in ozonated human serum upregulation of ho-1 in endothelial cells. Toxicol. Appl. Pharmacol. 2013;267:30–40. doi: 10.1016/j.taap.2012.12.001.
    1. Bocci V., Aldinucci C., Mosci F., Carraro F., Valacchi G. Ozonation of human blood induces a remarkable upregulation of heme oxygenase-1 and heat stress protein-70. Mediat. Inflamm. 2007;2007:26785. doi: 10.1155/2007/26785.
    1. Martinez-Sanchez G., Delgado-Roche L., Diaz-Batista A., Perez-Davison G., Re L. Effects of ozone therapy on haemostatic and oxidative stress index in coronary artery disease. Eur. J. Pharmacol. 2012;691:156–162. doi: 10.1016/j.ejphar.2012.07.010.
    1. Di Filippo C., Luongo M., Marfella R., Ferraraccio F., Lettieri B., Capuano A., Rossi F., D’Amico M. Oxygen/ozone protects the heart from acute myocardial infarction through local increase of enos activity and endothelial progenitor cells recruitment. Naunyn-Schmiedeberg’s Arch. Pharmacol. 2010;382:287–291. doi: 10.1007/s00210-010-0545-2.
    1. Barone A., Otero-Losada M., Grangeat A.M., Cao G., Azzato F., Rodriguez A., Milei J. Ozonetherapy protects from in-stent coronary neointimal proliferation. Role of redoxins. Int. J. Cardiol. 2016;223:258–261. doi: 10.1016/j.ijcard.2016.07.177.
    1. Calabrese E.J. Hormetic mechanisms. Crit. Rev. Toxicol. 2013;43:580–606. doi: 10.3109/10408444.2013.808172.
    1. Zhang J., Guan M., Xie C., Luo X., Zhang Q., Xue Y. Increased growth factors play a role in wound healing promoted by noninvasive oxygen-ozone therapy in diabetic patients with foot ulcers. Oxidative Med. Cell. Longev. 2014;2014:273475. doi: 10.1155/2014/273475.
    1. Coppola L., Giunta R., Verrazzo G., Luongo C., Sammartino A., Vicario C., Giugliano D. Influence of ozone on haemoglobin oxygen affinity in type-2 diabetic patients with peripheral vascular disease: In vitro studies. Diabete Metab. 1995;21:252–255.
    1. Verrazzo G., Coppola L., Luongo C., Sammartino A., Giunta R., Grassia A., Ragone R., Tirelli A. Hyperbaric oxygen, oxygen-ozone therapy, and rheologic parameters of blood in patients with peripheral occlusive arterial disease. Undersea Hyperbar. Med. J. Undersea Hyperbar. Med. Soc. Inc. 1995;22:17–22.
    1. Mehraban F., Seyedarabi A., Seraj Z., Ahmadian S., Poursasan N., Rayati S., Moosavi-Movahedi A.A. Molecular insights into the effect of ozone on human hemoglobin in autohemotherapy: Highlighting the importance of the presence of blood antioxidants during ozonation. Int. J. Biol. Macromol. 2018;119:1276–1285. doi: 10.1016/j.ijbiomac.2018.08.028.
    1. Coppola L., Lettieri B., Cozzolino D., Luongo C., Sammartino A., Guastafierro S., Coppola A., Mastrolorenzo L., Gombos G. Ozonized autohaemotransfusion and fibrinolytic balance in peripheral arterial occlusive disease. Blood Coagul. Fibrinol. Int. J. Haemost. Thromb. 2002;13:671–681. doi: 10.1097/00001721-200212000-00002.
    1. Di Paolo N., Bocci V., Salvo D.P., Palasciano G., Biagioli M., Meini S., Galli F., Ciari I., Maccari F., Cappelletti F., et al. Extracorporeal blood oxygenation and ozonation (eboo): A controlled trial in patients with peripheral artery disease. Int. J. Artif. Organs. 2005;28:1039–1050. doi: 10.1177/039139880502801012.
    1. Biedunkiewicz B., Tylicki L., Nieweglowski T., Burakowski S., Rutkowski B. Clinical efficacy of ozonated autohemotherapy in hemodialyzed patients with intermittent claudication: An oxygen-controlled study. Int. J. Artif. Organs. 2004;27:29–34. doi: 10.1177/039139880402700107.
    1. De Monte A., van der Zee H., Bocci V. Major ozonated autohemotherapy in chronic limb ischemia with ulcerations. J. Altern. Complement. Med. (N. Y.) 2005;11:363–367. doi: 10.1089/acm.2005.11.363.

Source: PubMed

Sponsor e collaboratori

Condizioni mediche

Interventi farmacologici

3
Sottoscrivi