key: cord-0759664-ijqrt7no authors: Vorobjeva, Nina V.; Sud'ina, Galina F.; Chernyak, Boris V. title: Mitochondria Are Potential Targets for the Development of New Drugs Against Neutrophilic Inflammation in Severe Pneumonia Including COVID-19 date: 2021-01-29 journal: Front Pharmacol DOI: 10.3389/fphar.2021.609508 sha: c3c9e18fce5732a7d5f9d71ee0a403e6be6353d0 doc_id: 759664 cord_uid: ijqrt7no nan When activated, leukocytes accumulating in the lungs cause damage to the capillary endothelium and alveolar epithelium. Destruction of blood vessel endothelial cells can lead to blood coagulation and strokes (Ackermann et al., 2020) . The attachment of neutrophils is mediated by adhesion molecules ICAM1, VCAM, etc., exposed on the surface of endothelial cells. The expression of these molecules is induced by inflammatory cytokines through the activation of the transcription factor NF-kB. We recently found that the expression of adhesion molecules is dependent on the production of mitochondrial ROS (mtROS), which contribute to NF-kB activation (Zinovkin et al., 2014; Galkin et al., 2016; Zakharova et al., 2017) . Moreover, mtROS are critical for the increase in endothelium permeability and endothelial cell apoptosis induced by the inflammatory cytokine TNF (Galkin et al., 2016) . The mitochondria-targeted antioxidants SkQ1 (10-(6′-methylplastoquinonyl) Decyltriphenylphosphonium) and SkQR1 (10-(6′plastoquinonyl) decylrhodamine 19) protect endothelial cells in vitro and prevent increased expression of adhesion molecules and the lethal effect of TNF in a mouse model of systemic inflammatory syndrome (Zakharova et al., 2017) . The mechanism of increased production of mtROS in the endothelium is not clear, but in the related model of endothelial stimulation with angiotensin II this mechanism has been shown to depend on mitochondrial permeability transition pore opening (mPTP) (Itani et al., 2016) . Inhibitors of the mPTP are currently being developed and studied as potential drugs against cardiovascular diseases (Briston et al., 2019) . It is possible that these drugs, when combined with mitochondria-targeted antioxidants, could be effective in preventing endothelial damage in a variety of inflammatory pathologies including pneumonia and COVID-19. Our recent studies have shown that mtROS play a key role in neutrophil activation (Vorobjeva et al., 2017; Vorobjeva et al., 2020) . The mitochondria-targeted antioxidant SkQ1 inhibited degranulation and ROS production induced by the chemoattractant fMLP via G-protein coupled receptor. It was concluded that mtROS are involved in the assembly and activation of the multicomponent enzyme complex NADPH oxidase (NOX2), which is the main source of ROS in neutrophils. The same cross-talk between mtROS and NADPH oxidase has been described in the endothelial cells (Nazarewicz et al., 2013) . As in the endothelium, mtROS production in human neutrophils depends on the opening of mPTP (Vorobjeva et al., 2020) . One of the important consequences of neutrophil activation is a delay in spontaneous apoptosis. This effect was blocked by mitochondria-targeted antioxidants (Vorobjeva et al., 2017) , so it is possible that these agents could not only inhibit the damaging activity of neutrophils, but also reduce their number in inflammatory lesions. Our experiments with the mitochondria-targeted antioxidant SkQ1 showed its potential efficacy against NETosis (Vorobjeva et al., 2020) . It was shown that NETs formation induced by Ca 2+ ionophore A23187 depends on the mPTP opening and the generation of mtROS. NETosis in this model was mediated by mtROS-dependent activation of NADPH oxidase. The massive production of ROS by NADPH oxidase, in turn, stimulated the opening of mPTP and mtROS generation. We have demonstrated that SkQ1 interrupted this vicious circle effectively neutralizing mtROS (Vorobjeva et al., 2017; Vorobjeva et al., 2020) . The antioxidant MitoQ, which is structurally similar to SkQ1, suppressed NETosis in the mouse model of systemic lupus erythematosus (Fortner et al., 2020) . Various therapeutic approaches have been developed to inhibit neutrophils accumulation in the foci of inflammation, their activation and NETosis, as well as factors destroying NETs. They include anticytokine therapy directed against IL-1β (Anakinra; a recombinant IL-1β receptor antagonist is currently in clinical trials against COVID-19; https://clinicaltrials.gov: NCT04324021, NCT04330638, NCT02735707. 2020.), and NETosis may be one of its targets. Low molecular weight IL-8/ CXCR2 antagonists have been tested in clinical trials for asthma, chronic obstructive pulmonary disease (COPD) and influenza, and have shown suppression of pulmonary neutrophilia and a decrease in the signs of NETosis (Narasaraju et al., 2020) , but they have not been tested in COVID-19 trials. Among NETosis inhibitors, especially extensive research and testing has been conducted with NE inhibitors. The first of these, Sivelestat, has been approved for use against ARDS in Japan and South Korea, but meta-analysis of clinical data did not confirm its effectiveness (Tagami et al., 2014) . New generation NE inhibitors have been clinically tested for the treatment of COPD and may hold promise for COVID-19, as well as recombinant DNAse I that degrades NETs (Narasaraju et al., 2020) . The in vitro experiments have shown that NETosis can be prevented with the microtubule inhibitors. This group of drugs includes the oldest antiinflammatory drug Colchicine, which, despite its strong cytotoxicity, is successfully used in small doses to treat acute gout and some other inflammatory diseases (Leung et al., 2015) . Clinical trials of the efficacy of Colchicine against COVID-19 are currently underway (https://clinicaltrials.gov: NCT04326790, NCT04328480, NCT04322565, NCT04322682.2020.). Leukotrienes, metabolites of arachidonic acid produced in the 5-lipoxygenase (5-LOX) pathway, are lipid mediators of inflammation involved in asthma and COPD, which are also considered potential targets for COVID-19 therapy (Funk and Ardakani, 2020) . The 5-LOX pathway is activated in many diseases and triggers inflammatory responses that are not affected by glucocorticoids. Leukotriene B4, produced from leukotriene A4 by the soluble leukotriene A4 hydrolase, is a potent neutrophil chemoattractant that mediates the airway neutrophilia seen in severe COVID-19 (Wang et al., 2020b; Barnes et al., 2020) . Another metabolite of arachidonic acid, epoxy fatty acids (EpFA), exhibits anti-inflammatory properties Frontiers in Pharmacology | www.frontiersin.org January 2021 | Volume 12 | Article 609508 in contrast to leukotrienes. Prevention of NF-kB activation by EpFA can be mediated by inhibition of mPTP and subsequent production of mtROS (Wagner et al., 2020) . To promote the accumulation of EpFA, inhibitors of soluble epoxide hydrolase (sEH), which converts EpFA to less active metabolites, have been developed (Wagner et al., 2020 ). An excellent effect in the resolution of inflammation was achieved by the double inhibition of leukotriene A4 hydrolase and sEH (Hefke et al., 2020; Hiesinger et al., 2020) . Dual 5-LOX/sEH inhibition significantly suppressed leukocyte activation (Meirer et al., 2016) , and neutrophil infiltration (Garscha et al., 2017) . Another approach to the treatment of COVID-19, based on the use of the cysteinyl leukotriene receptor 1 (CysLT1) antagonist Montelukast, was recently proposed (https:// clinicaltrials.gov/ct2/show/NCT04389411). In a small group of elderly patients with asthma, the use of Montelukast reduced the risk of SARS-CoV-2 infection (Bozek and Winterstein, 2020) . We hypothesize that mitochondria-targeted antioxidants and mPTP inhibitors may have beneficial effects in patients with severe COVID-19. These agents can be used alone or in the combination with other drugs. For example, the antioxidant N-acetylcysteine has recently been shown to enhance the action of Sivelestat against inflammatory pathology (Raevens et al., 2020) . In summary, mitochondria appear to be a promising target for further drug development against severe pneumonia including COVID-19. 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The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.Copyright © 2021 Vorobjeva, Sud'ina and Chernyak. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.