Endothelial activation and oxidative stress in pulmonary endothelial cells following severe COVID-19.

During the alpha wave of SARS-CoV-2 (SCA), the number of ICU-hospitalized COVID-19 patients was high. In a dynamic co-evolution, the virulence of the virus changed during the Omicron wave (SCO). Initial findings of COVID-19 indicate that infection with SARS-CoV-2 leads to endothelial dysfunction through inflammatory pathways, oxidative stress, and alterations in vascular homeostasis. Upregulation of adhesion molecules (ICAM-1 and VCAM-1) in response to pro-inflammatory cytokines helps immune cell migration and vascular inflammation. Furthermore, oxidative stress disrupts the balance between the oxidant and antioxidant systems. Excessive NOX2 activity promotes ROS production and Nrf2 suppression, leading to endothelial dysfunction. Also, alterations in vascular homeostasis and increased vWF secretion heightens the risk of thrombosis, while dysregulated iNOS contributes to further endothelial damage. Considering that endothelial cell dysfunction can promote various disease processes, including thrombosis and atherosclerosis, this study evaluates the main changes in the host lung endothelium in COVID-19 during this co-evolution. The direct effects of SCA and SCO on endothelial function were investigated in bronchoalveolar lavage fluid (BALF) samples obtained from leftover specimens of COVID-19 patients, which were compared to the control group. In the BALF samples of patients, key endothelial molecules involved in immune cell recruitment, such as iNOS, Nrf2, NOX2, vWF, ICAM-1, and VCAM-1, were evaluated using RT-qPCR and Western blotting. In severe COVID-19, ICAM-1 and VCAM-1 were upregulated compared to the control group. Furthermore, vWF expression was also upregulated. A significant increase in iNOS gene expression was observed during the Omicron wave. Although NOX2 expression increased during the SCA and SCO waves, Nrf2 expression was downregulated in both SARS-CoV-2 waves. Overall, during the co-evolution of the virus and host, disruption of endothelial cell function can affect selective immune cell recruitment and, in the late phase, lead to local vascular dysfunction and severe outcomes such as hospitalization. Targeting key endothelial molecules for therapy can not only alter immune cell recruitment but also prevent endothelial dysfunction throughout the body.