Bronchial inflammation is principal focus in asthma pathogenesis and asthma treatment. Disbalance between free oxygen radicals and anti-oxidative defense is important in control of airway inflammation. Free oxygen radicals have strong contribution in the pathogenesis of allergic asthma. The modulation of oxidation and antioxidative defense represents new therapy in complex management of asthma. Co-Q10 is one of the main supplementations that has important effect in antioxidative defense [17]. In this study, we observed that treatment with Co-Q10 and other additive supplementations can control allergic rhinitis and allergic asthma pathophysiology related factors and Co-Q10 may be useful in the treatment of allergic diseases. Combined anti-inflammatory therapy is preferred in order to minimize the manifestations of adverse reactions. In this study we used Co-Q10 with two part of combined therapy.
Co-Q10 is an essential factor that contributes to the development of mitochondrial pathology, MRC function, and allergic inflammation. Dietary disorders and hereditary factors contribute to the development of acquired Co-Q10 deficiency, which lead to mitochondrial abnormalities in the asthmatic patients [18, 19]. Mitochondrial abnormalities are related with oxidative stress that causes damage to a variety of biomolecules in membranes, proteins, and DNA, which contribute to asthmatic airways injury [18, 19]. Co-Q10 an integral part of the mitochondrial electron transport chain, scavenges free radicals and has anti-inflammatory properties. Corticosteroids as effective drugs in the asthma treatment inhibit inflammatory cytokine production. In asthma, Co-Q10 was associated with reduction of the corticosteroid dose [19, 20]. In this study, Co-Q10 treatment reduced main type 2 cytokines (IL-4, 5 and 13) and enhanced main type 1 cytokine (INF-γ) in asthma and rhinitis groups. Therefore, Co-Q10 can control inflammation in airway and allergic reactions in upper and lower airways and modulate immune response in lung. This treatment significantly controls IgE, histamine, Cyc-LT and LTB4 as main allergic bio-factors and allergic response mediators.
Although the importance of Co-Q10 in mitochondrial function is widely recognized, Co-Q10 low level in serum of asthmatic patients has been reported [17]. However, the oxidative phosphorylation and ATP production are dependent upon the MRC complexes function and it was reported that Co-Q10 deficiency has pathologic effect on MRC function. Co-Q10 is an essential MRC component and MRC dysfunction is frequently associated with deficiency of Co-Q10, which may lead to mitochondria degradation. Co-Q10 deficiency also contributes to increased reactive oxygen species generation and in result, inflammation processing [18]. In this study, we found that Co-Q10 can modulate MRC and reactive oxygen species related genes. This effect was emphases when it was with supplementary treatment. Also, eosinophilic inflammation related genes such as eotaxin, CCL11 and CCL24 genes expression have been controlled and harnessed by Co-Q10 treatment and especially when Co-Q10 was used with Mg-S and O-3. These treatments can control mucus secretion and goblet cell hyperplasia, which are main obstruction factors of airway. On the other hand, when Co-Q10 has Mg-S and O-3 as additive supplementation, peribronchial and perivascular eosinophilic inflammation and also eosinophil present in BALf were decreased significantly. Three treatment protocols can reduce EPO and therefore, may be important treatment in control of eosinophilic injury in bronchi. In the presented investigation, effect of Co-Q10 on airway inflammation was survived and the effect of Co-Q10 on eosinophilic injury in airways was not studied and needs future investigations.
Co-Q10 represents an important member of the antioxidative potential and plays a decisive role in the cell energy production and in the scavenger activity. In the study by Gazdík et al., it was reported that Co-Q10 concentrations was decreased in plasma of asthmatic patients compared with healthy volunteers [17]. Therefore, increased level of Co-Q10 can have protective effect on pulmonary functions.
The Nrf2 is a redox-sensitive basic leucine zipper transcription factor and involved in the transcriptional regulation of antioxidant genes. Nrf2 disruption increases expression of the Th2 cytokines and enhances asthma severity. Nrf2 is activated in response to allergen, induces transcriptional of antioxidant genes that provide resistance against the asthma development [21]. It has been reported that Nrf2 deficiency enhances bronchial inflammation in asthma. Disruption of Nrf2 also leads to eosinophils increases in lung tissues, airway remodeling, AHR, goblet cell hyperplasia, and level of Th2 cytokines. The Nrf2 signaling plays an essential role in broncho-protection [22]. In our study, Co-Q10 treatment can increased Nrf2 expression and significantly enhanced Nrf2 gene activation. Therefore, Co-Q10 treatment control inflammation and in result, oxidative stress injury in lung.
Nrf2 expression was associated with glutathione redox and the duration of asthma, the Nrf2 pathway is disrupted. Decreased Nrf2expression in asthmatic lung tissue associated with increased inflammation and steroid resistance [23]. In addition to, Nrf2-deficiency up-regulates IL-33 response and administrates allergy. Nrf2 activation suppresses IL-33 releasing and attenuates bronchial inflammation [24]. So, activation of Nrf2 expression leads to control of Th2 cytokines and upper hand of these cytokines (IL-33), and can be attenuate allergic and inflammation related agents and allergic rhinitis and asthma.
Co-Q10 as supplementary agent, has anti-inflammatory and antioxidant effects. Co-Q10 increases the Nrf2 expression. The Nrf2 over-expression controls allergic and inflammatory factors. On the other hand, the Nrf2 regulates the antioxidant related enzymes and increased anti-oxidative activity of this system. In the COVID-19 pandemy, one of the main dangerous complications of SARS-Cov2 infection is ARDS that increases morbidity and mortality of COVID-19 positive patients. ARDS is caused by pulmonary inflammation, and damage. ARDS may be suppressed by controlling of inflammation and cell damage by increasing anti-inflammatory and antioxidant factors. Co-Q10 supplementation with other anti-COVID-19 drugs, might be beneficial on patients with ARDS [22, 25]. Moreover, two interactional factors, oxidative stress and inflammation involve in ARDS and activation of Nrf2 can control oxidative stress and inflammation in ARDS [22]. Therefore, Nrf2 activation with Co-Q10 and other treatments can be effective drug in control and treatment of ADRS in COVID-19. According to our search, there was no research about effect of Co-Q10 on ARDS of the COVID-19 mouse model. Since, there was no related research, it is suggested that future researches have focused on effect of Co-Q10 on ARDS and COVID-19 lung inflammation.
ARDS caused by SARS-Cov2 is followed by alveolar cells damage and lung fibrosis and the host immune response (with cytokine storm) and inflammation is a crucial determinant of disease outcome. Cytokine storm is associated with pulmonary inflammation, and respiratory system damage and ARDS in molecular glance, is presented by cell death and production of pro-inflammatory cytokines. Regulating of this pathway may be useful in treatment of COVID-19 patients with harnessing of ARDS. Nrf2 as cytoprotective transcription factor can boost endogenous cellular defenses, control inflammation, restore redox homeostasis and also facilitate tissue repair. Nrf2 binds to antioxidant response elements, and regulates proteins production that are involved in cellular redox homeostasis, detoxification, cell damage repair, and metabolic balance. Importantly, activated Nrf2 is involved in preserving lung architecture in response to inflammation, and has strong therapeutic effects ARDS. Moreover, Nrf2 plays a role in the inflammation resolution by repressing IL1-β, IL6, TNF-α and other pro-inflammatory cytokines (cytokine storm inhibition). Also, Nrf2 induces tissue repair genes, anti-oxidative protein, CD36 as scavenger receptor, and IL-17D as protector against viral infections [25]. In COVID-19, SARS-CoV-2 infection depends the host cell factors ACE2 and TMPRSS2. Virus binds to the cell via ACE2 receptors and spike protein must be cleaved by serine protease TMPRSS2 for enter to the cell. Nrf2 as a regulator of respiratory viral infections susceptibility, down-regulates ACE2 (a surface receptor) and TMPRSS2 activates the spike protein for SARS-Cov-2 entry into host cells. Nrf2 has ability to impede viral entry, slows viral replication, and reduces inflammation and mortality in respiratory viral infection. It may prove suitable treatment for COVID-19 cases [26]. Nrf2 activation reduce lung cells damage in COVID-19 patients and Inhibits virus penetration. Moreover, the Nrf2 activation improves phagocytosis and clearance through a mechanism is independent of the intracellular-antioxidant glutathione. Nrf2 regulates GSH via controlling and modulatory release of γ-glutamyl cysteine ligase and also, induces anti-oxidant enzymes such as NQO1, HO-1, SODs, Grx1, and Trx1 production [27]. In this study, we hypothesis that pharmacological Nrf2 activation in the context of SARSCov-2 infection can inhibit ARDS, protect lung cells, act as anti-inflammation, harness cytokine storm, inhibit viral integration, control oxidation stress by ROS scavenging, and present other cytoprotective effects. Therefore, in COVID-19, Nrf2 not only prevents of viral iterance, but also, harnessing ARDS and hyper-inflammation by control cytokines storm and oxidative stress, and repairs lung tissue that needs more investigation in future.
Co-Q10 as a main supplementation has anti-inflammatory effect when used with Mg-S and O-3 as combined therapy. It can activate Nrf2 expression in response to allergen, induces resistance against the asthma development and plays an important role in protection on upper and lower airways against allergic response and pathology, control inflammation and moreover, ARDS. Because, Co-Q10 has anti-inflammatory and antioxidant effects, might be beneficial for ARDS by controlling of lung inflammation and cell damage in the COVID-19 patients.