I/R injury, a major cause of lung transplant failure, occurs predominantly due to recruitment of polymorphonuclear neutrophils (PMN) into the (donor) lung endothelium from the recipient's circulation post‐transplant surgery. Endothelial signaling is pivotal in driving the recruitment and adherence of PMN to the vascular wall. We used our past research, expertise and knowledge on pulmonary endothelial mechanosignaling (wherein we unraveled the cascade associated with ischemia to show a KATP closure induced endothelial NADPH oxidase 2 or NOX2 activation and reactive oxygen species, ROS, production) to evaluate how stop and restart of flow lead to PMN adherence. We show here (using in vitro, in situ and in vivo models of lung I/R) that endothelial NOX2 activation (as monitored by ROS production in vitro, in situ and oxidative damage in vivo) is linked to expression of adhesion molecules (CAMs) and to the recruitment of PMN. The mechanosignal can be blocked by preventing NOX2 activation either directly by blocking NOX2 assembly (with apocynin or with MJ33 that blocks the PLA2 activity of peroxiredoxin 6) or by blocking the upstream events (KATP channel); this has potential application in lung transplantation.