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Introduction Recent research suggests that endothelial activation plays a role in COVID-19 pathogenesis by promoting a pro-coagulative and pro-inflammatory state. However, the mechanism by which the endothelium is activated in COVID-19 is unclear. Objective To investigate the mechanism by which COVID-19 activates the pulmonary endothelium. Hypothesis The pulmonary endothelium generates reactive oxygen species (ROS) upon exposure to the ?inflammatory load? of the systemic circulation. Methods COVID-19 was recreated in vitro and ex vivo, by exposing human lung endothelial cells (EC) or donor human lung slices (human precision-cut lung slices or huPCLS) to medium supplemented with serum from COVID-19 affected subjects. Sera were acquired from patients with COVID-19 infection admitted to the Intensive Care Unit of the Hospital at the University of Pennsylvania. ROS (fluorescent dye, CellROX) and intercellular adhesion molecule (ICAM-1) levels were assessed by fluorescence labeling and imaging. Results Both EC activation (as monitored by ROS production) and pro-inflammatory phenotype (as assessed by ICAM-1), were significantly higher with COVID-19 as compared to normal subjects. Conclusions The endothelium is activated with COVID-19 via ROS production;thus, the ROS produced drive a pro-inflammatory phenotype by inducing the expression of ICAM-1, a pivotal marker of endothelium inflammation. As ROS mediates EC activation and inflammation during COVID-19, ROS blockade could be a therapeutic target in maintaining vascular health.
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BACKGROUND: Pulmonary hyperinflammation is a key event with SARS-CoV-2 infection. Acute respiratory distress syndrome (ARDS) that often accompanies COVID-19 appears to have worse outcomes than ARDS from other causes. To date, numerous lung histological studies in cases of COVID-19 have shown extensive inflammation and injury, but the extent to which these are a COVID-19 specific, or are an ARDS and/or mechanical ventilation (MV) related phenomenon is not clear. Furthermore, while lung hyperinflammation with ARDS (COVID-19 or from other causes) has been well studied, there is scarce documentation of vascular inflammation in COVID-19 lungs. METHODS: Lung sections from 8 COVID-19 affected and 11 non-COVID-19 subjects, of which 8 were acute respiratory disease syndrome (ARDS) affected (non-COVID-19 ARDS) and 3 were from subjects with non-respiratory diseases (non-COVID-19 non-ARDS) were H&E stained to ascertain histopathological features. Inflammation along the vessel wall was also monitored by expression of NLRP3 and caspase 1. RESULTS: In lungs from COVID-19 affected subjects, vascular changes in the form of microthrombi in small vessels, arterial thrombosis, and organization were extensive as compared to lungs from non-COVID-19 (i.e., non-COVID-19 ARDS and non-COVID-19 non-ARDS) affected subjects. The expression of NLRP3 pathway components was higher in lungs from COVID-19 ARDS subjects as compared to non-COVID-19 non-ARDS cases. No differences were observed between COVID-19 ARDS and non-COVID-19 ARDS lungs. CONCLUSION: Vascular changes as well as NLRP3 inflammasome pathway activation were not different between COVID-19 and non-COVID-19 ARDS suggesting that these responses are not a COVID-19 specific phenomenon and are possibly more related to respiratory distress and associated strategies (such as MV) for treatment.