How the ozone therapy can influence the redox metabolism and the inflammatory process of hepatocytes in murine models? A systematic review

Abstract

The hepatocyte plays an important role in the oxidative balance by its direct activation or by the indirect activation of other cells in the liver tissue, such as Kupfer cells and neutrophils. All these characteristics make liver cells an important factor to understand the main mechanisms involved in the tissue oxidative stress process. In this sense, ozone therapy is a promising tool for the treatment of liver damage, since it is known to control the release of free radicals and increase the expression of antioxidant enzymes. Thus, this work aimed to investigate the main intracellular pathways activated after exposure to ozone therapy, taking into account the measurement of antioxidant enzymes and markers of oxidative stress, secondary to the action of free radicals. This systematic review was performed based on the PRISMA guidelines and using a structured search in MEDLINE (PubMed), Scopus, and Web of Science. The included studies are limited to those that used ozone therapy to control tissue oxidative stress in liver tissue in murine models. The main activated cellular pathways, ozone dose, concentration, and the relationship between oxidative and inflammatory markers were extracted and compared when possible. Bias analysis and methodological quality assessments were examined using the SYRCLE Risk of Bias tool. Nineteen studies were selected. Our results showed that exposure to ozone therapy has a protective effect on liver tissue, promoting a decrease in inflammatory tissue, and consequently decreases oxidative stress in hepatic tissue. Regarding the control of inflammation, the main markers analyzed were TNF-α and IL1-β. Morphological changes caused in the tissue by the action of free radicals were hepatocellular degeneration, steatosis, periportal inflammation, apoptosis, and necrosis. Our results showed that Ozone treatment promoted the reduction of oxidative markers such as malondialdehyde (MDA), carbonyl protein (CP), hydrogen peroxide (H 2 O 2 ), 4-HDA (hydroxynonental) conjugated diene and pro-oxidant enzymes such as myeloperoxidase (MPO), xanthine oxidase (XOD), and NADPH oxidase (Nox). In addition, ozone therapy promoted an increase in the antioxidant enzymes Superoxide dismutase (SOD), Catalase (CAT), and Glutathione (GST). The morphological consequences of the control of these intracellular pathways were the reduction of the tissue inflammatory process, and consequently, the reduction of degenerations and necrosis areas after treatment with ozone therapy. We believe that ozone therapy is an effective therapy to control oxidative stress and tissue inflammation by stimulating redox balance in liver cells. Considering a detailed assessment of reports and methodological quality, the current preclinical evidence presents a high risk of bias concerning animal models, dosage, and concentration of ozone therapy. These results show that much still needs to be studied in this area so that the results found in pre-clinical models can be translated into the clinical context. However, we hope that our critical analysis will be useful in mitigating the risk of bias in future studies. This study is registered on the PROSPERO platform (CRD42021264362). Keywords: Ozone therapy. Oxidative stress. Antioxidant enzymes. Liver. Inflammation