IntroductionRecent 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.ObjectiveTo investigate the mechanism by which COVID‐19 activates the pulmonary endothelium.HypothesisThe pulmonary endothelium generates reactive oxygen species (ROS) upon exposure to the “inflammatory load” of the systemic circulation.MethodsCOVID‐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.ResultsBoth 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.ConclusionsThe 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.