COVID-19'un patogenezinde ve şiddetinde reaktif oksijen ve nitrojen türlerinin rolü ve insan bronşiyal epitel organoidlerinde SARS-CoV-2 ile PM2.5 arasındaki etkileşim

The coronavirus disease 2019 (COVID-19) has caused significant mortality and morbidity worldwide. The disease is associated with increased inflammatory status that can lead to pneumonia, cytokine storm, and acute respiratory distress syndrome (ARDS). Studies suggest that respiratory viral infections may cause redox imbalance and oxidative stress; however, the role of these phenomena in the pathogenesis of COVID-19 is not known. Although an association between increased levels of air pollutants including particulate matter (PM) and COVID-19 morbidity and mortality has been reported, the underlying mechanisms are not clear. The aims of my studies were; (i) to investigate the effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and PM  2.5µm (PM2.5) on the production of reactive oxygen species (ROS) and reactive nitrogen species (RNS), activation of pathways involved in cell death mechanisms, and the release of inflammatory cytokines in human bronchial epithelial organoids (HBEOs), and (ii) to validate markers of ROS/RNS and inflammation in plasma of COVID-19 patients. My study findings demonstrated that PM2.5 increased SARS-CoV-2 viral load in HBEOs, which was prevented by inhibitors of ROS (N-acetyl cysteine, NAC) and RNS (NG-Monomethyl-L-arginine acetate salt, L-NMMMA). Furthermore, PM2.5 induced oxidative/nitrosative stress in HBEOs that led to activation of the Nuclear Factor E2-Related Factor 2/ Kelch-like ECH-associated protein 1 (NFE2L2/KEAP1) pathway stimulating antioxidant genes NAD(P)H dehydrogenase (NQO1), and heme oxygenase 1 (HMOX1) together with pro-oxidant nitric oxide synthase 3 (NOS3). ROS/RNS inhibitors were effective in the suppression of oxidative/nitrosative stress. Finally, PM2.5 and SARS-CoV-2 activated the cell death mechanisms including ferroptosis and apoptosis in HBEOs. The analysis of plasma obtained from COVID-19 patients showed increased production of ROS/RNS and inflammatory cytokines (IL-6, IL-8), especially in severe patients. My study findings suggest that SARS-CoV-2 can lead to cellular inflammation and death by mechanisms involving oxidative/nitrosative stress and that this can be induced by ambient PM2.5. Moreover, 8-isoprostane (ROS indicator) and nitrite (RNS indicator) can be used as novel plasma biomarkers in the severity of COVID-19.