3. Discussion
acute infection, death, TNF-α, tumor necrosis, multiorgan dysfunction, immune disorders, autoimmune diseases, infections, MOF, organ dysfunction, inflammation, organic dysfunction, infection, organ failure, septic shock, multiorgan failure, sepsis
AUTOIMMUNE DISEASES, IMMUNE DISORDER, EVENTS, OXIDATIVE STRESS, INFLAMMATORY RESPONSES, PROLIFERATION, INFLAMMATION, MOF, INFECTIONS, HYPOTENSION AND SHOCK, MULTIORGAN FAILURE, IMMUNOPATHOLOGY, PATHOGENESIS, INFLAMMATORY RESPONSE, PATHOLOGICAL PROCESS, CNS INFECTIONS, INFECTION, SEPSIS, ACUTE INFECTION, TUMOR NECROSIS, DISEASE, INFECTIOUS PROCESS, SEPTIC SHOCK
The control of the activation of pathophysiological mechanisms such as oxidative stress, and innate and adaptive inflammatory response in septic shock is vital [On the other hand, the participation of pathogen-derived molecular patterns (PAMPs) and damage-associated molecular patterns (DAMPs), recognized by specific receptors on the cell surface, initiate the transcription cascade of inflammatory molecules due to the translocation of the nuclear factor NF-kβ in activated cells.Imbalance requires early therapeutic management [Cytokines activate and inhibit cellular functions by negatively regulating effector mechanisms and restoring homeostasis through the release of cytokines IL-10 and transforming growth factor-β. They also regulate protein deposition in the extracellular matrix and angiogenesis [The effects of the use of antioxidant therapy in patients with septic shock and its effect on cytokines were among the objectives of this study since we have previously reported reduced biomarkers of oxidant stress with the use of this therapy. Furthermore, there was better disease control in patients with COVID-19. Although the results in previous works are good, experimental and clinical studies are still required to confirm this hypothesis [In this sense, cytokines involved in innate immunity are attractive targets for therapeutic intervention [In this study, we support the hypothesis raised by us and other researchers that the function of cytokines changes with the use of antioxidant therapy. We found an increase in the level of IL-2 after treatment with Vit E, NAC, and MT. Only Vit E showed a statistically significant difference. This finding coincides with a previous one in children undergoing dialysis treatment, where they combined NAC with Vit E and demonstrated regulation of the cellular redox state and modulation of the cytokine profile. That study also found a reduction in organ damage at the level of the kidney in patients with septic shock [The combined use of Vit E and NAC to stimulate the production of IL4 had a regulatory effect on oxidative stress, inflammation, and organ failure in experimental studies with an animal model [NAC increased IL-10, which has regulatory properties. The increase in IL-10 levels due to the use of antioxidants is an important finding since there is multiorgan dysfunction that involves uncontrolled production of reactive oxygen species (ROS) and a cytokine storm in septic shock. At the same time, exhaustion of antioxidants that contribute to the progression to septic shock occurs. Macrophages secrete proinflammatory and anti-inflammatory mediators during the infectious process. The binding of lipopolysaccharide (LPS) to Toll-like receptor 4 (TLR4) releases TNF-α, which initiates proinflammatory events through tumor necrosis factor receptor 1 (TNFR1) signaling, which is an effect of IL-10 [IL-12 has a regulatory function and there was no association between its levels and severity of the disease in a study of children with septic shock [The increase in IL-12 found in this study has particular importance given that the most important function of IL-12 is the induction of gamma interferon (IFN), which is a mediator in viral, fungal, bacterial, and parasitic resistance. The induction of IL-12 triggered by microbial products is a potent stimulus for IFNy, which leads to the quick control of the infection by these agents. However, if the response is not controlled, the synthesis of IL-12 can result in an excessive activation of the immune system which causes damage to the host tissue and even death. This occurs in autoimmune diseases and/or septic shock.The Induction of IL-12 during acute infection is crucial to initiate the synthesis of INFy by NK cells and T lymphocytes, and mediators of resistance against viruses, bacteria, fungi, and parasites. In several animal models, IL-12 has been used as immunotherapy to protect cellular immunity and to control or reject inappropriate responses to pathogenic infections in organisms with immune disorders. In any case, increasing its concentration can be beneficial. However, the excess IL-12 response appears to be responsible for some problems observed during severe microbial infections. Under these conditions, IL-12 antagonists have attenuated immunopathology and prevented death. The toxic effects of the proposed therapy with IL-12 were observed in mice, and therefore its use as therapy in humans is controversial. A study with different doses is still necessary, or its combined use with antimicrobials with other molecules or with antioxidants [In this study, IL-6 showed elevated levels before antioxidant therapy. Levels decreased in patients treated with Vit C, MT, and NAC. However, this effect was similar in the control group. This finding coincides with that from a systematic cohort study of patients with sepsis, in which the therapy was only with antibiotics and considered Il6 as a possible predictor of response to this therapy. The study also documented the substantial interindividual variability in the induction of IL-6 during sepsis since it depends on the type of infection, type of bacteria, and origin of the organ involved. All patients in our study received antibiotics. Therefore, the change and difference observed with antioxidants based on this cytokine will require an appropriate methodological strategy to discern whether the antioxidant effect creates synergy with the impact or is only related to the antibiotic [Another regulatory cytokine involved in controlling the infectious process is TGF-β since it inhibits viral replication and cell proliferation. We found that all our patients had low levels of TGF-β before treatment, and levels increased in the group treated with antioxidants and in the control group. However, none showed a significant statistical difference; only the group treated with NAC had a clear trend of There is evidence for the complex pathogenesis of septic shock and LPS-induced re-actions. In recent years, mediators such as cytokines have aroused great interest for their role in inflammatory responses induced by LPS, TNFα, and IL-1 [The relevance of TGFB1 in septic shock has been studied in mouse macrophages, and it inhibits JNK activity stimulated by lipopolysaccharide (LPS). It might have a possible inhibitory mechanism on TGF-beta in the signaling of inflammatory responses induced by LPS [Several studies have demonstrated the involvement of proinflammatory cytokines in septic shock, and patients receiving standard treatment improve in intensive care units [High amounts of IL-1 and TNF-α are released during systemic inflammation, resulting in hypotension and shock. However, IL-1 is frequently undetectable and, when present, has little predictive value [On the other hand, results using antioxidants at the experimental level have shown that some have regulatory capacity on oxidative stress. MT has radical scavenging properties and protects cell membrane lipids, cytosol proteins, nuclear proteins, and mitochondrial DNA. In our research, it reduced LPO, similar to Galley’s findings [After release, plasma melatonin is rapidly distributed and transported to the mitochondria, acting as an antioxidant. In mammals, MT is an agonist of MT1 and MT2 receptors [GPx uses selenoprotein P as a cofactor and decreases during septic shock [One of the inducers of sepsis is endotoxin or lipopolysaccharide (LPS), which comes from Gram-negative bacteria and leads to sepsis and multiorgan dysfunction [The glutathione peroxidase enzyme metabolizes intermediates formed by aerobic metabolism, such as hydrogen peroxide; this reaction occurs in the cytosol and mitochondria, resulting in oxidized glutathione, which is reduced by glutathione reductase. GR employs NADPH as a cofactor, helping to recycle an oxidation–reduction [Glutathione is a tripeptide composed of three amino acids: glutamic acid, glycine, and cysteine. It plays a vital role in septic shock since it protects against damage caused by free radicals. Like glutathione, Vit E is a fat-soluble antioxidant [In this study, Vit C and Vit E decreased LPO. Vit E and MT increased the total antioxidant capacity. NAC, a direct precursor of glutathione, increased glutathione levels and improved multiorgan failure (MOF), in accordance with previous research [The effect of various antioxidants, such as NAC, MT, vitamins A, C, and E, enzyme cofactors (selenium and zinc), endogenous compounds (ubiquinone, α-lipoic acid, bilirubin, albumin, ferritin), and quercetin, can inhibit reactive nitrogen, oxygen species (ROS), and RNS [Innate cytokines are attractive targets for therapeutic intervention [In septic shock, interleukins are the first to increase, reaching a maximum peak at 2 h, when procalcitonin increases, and IL-6 and IL-8 levels decrease [In sepsis, organ dysfunction is potentially fatal, and it is caused by deregulation of the host response to infection. The pathological process is complex, and several cytokines participate in the damage mechanism, which, when dysfunctional, lead to an intertwined storm whose outcome worsens function and causes structural damage at the cellular, tissue, and organ level. The uncontrolled inflammation cascade requires regulation of both the cytokines involved and other intertwined mechanisms, such as the deregulation of oxidative stress, which requires simultaneous treatment and modulation to repair tissues and improve organ function.Standard therapy in sepsis includes hydroelectrolytic hemodynamic management and antibiotic therapy that essentially control the initial inflammatory pathophysiological damage. However, deregulation of oxidative stress must also participate and is necessary to improve organ dysfunction and interact in the modulation of some cytokines.Although there are limitations with using oxidative stress markers in emergency conditions, in this research we show that there is deregulation of oxidative stress in septic shock, which is related to cytokine storm, and that the complex interaction produced by treatment with antioxidants can improve organic dysfunction.A limitation of this study is that the sample size would have to be larger to confirm the statistical power for all cytokines.