Mitochondria Are Potential Targets for the Development of New Drugs Against Neutrophilic Inflammation in Severe Pneumonia Including COVID-19

A high neutrophil-to-lymphocyte ratio is associated with disease severity and poor prognosis in pneumonia progressing to acute respiratory distress syndrome (ARDS) (Steinberg et al., 1994) including COVID-19 (Coronavirus Disease-19) caused by the novel SARS-CoV-2 coronavirus (Wang et al., 2020a; Mehta et al., 2020). Extensive infiltration of neutrophils into the pulmonary capillaries as well as their extravasation into the alveolar space have been described in bronchoalveolar lavage (Steinberg et al., 1994) and in autopsy specimens (Barnes et al., 2020; Wang et al., 2020b). Neutrophils are the first line of defense against invading pathogens in the foci of inflammation, where they use effector functions such as phagocytosis, degranulation, and the formation of reactive oxygen species (ROS). Excessive activation of neutrophils results in the release of neutrophil extracellular traps (NETs) consisting of decondensed chromatin, «decorated» with myeloperoxidase (MPO), neutrophil elastase (NE), and other bactericidal proteins derived from intracellular granules (Brinkmann et al., 2004). The formation of NETs is usually accompanied by cell death, therefore, this process is called NETosis. Examination of patients with severe pneumonia (Twaddell et al., 2019) as well as patients infected with SARS-CoV-2 (Zuo et al., 2020) revealed an increased level of NETosis markers, such as cell-free DNA, MPO-DNA-complexes, citrullinated histone H3, and a marker of cell death lactate dehydrogenase. In the serum from patients with COVID-19 the concentration of cell-free DNA correlated with the content of neutrophils, the marker of the acute phase of inflammation C-reactive protein, and the marker of thrombosis D-dimer (Zuo et al., 2020). This serum induced NETosis in healthy donor blood in an in vitro system (Barnes et al., 2020; Zuo et al., 2020). One of the manifestations of COVID-19 is Kawasaki syndrome, a vasculitis that occurs in children and is accompanied by excessive NETosis (Yoshida et al., 2020). NETosis in COVID-19 can be caused by epithelial and endothelial cells affected with the virus, by activated platelets, and by inflammatory cytokines. At the same time, excessive NETosis is involved in the development of the «cytokine storm» and immunothrombosis, which are the main cause of severe complications associated with COVID-19 (Wang et al., 2020a; Barnes et al., 2020), as well as with H1N1 influenza and some other viral infections (Cantan et al., 2019).