Ventilator-induced Lung Injury (VILI) is associated with activated inflammatory signaling such as cytokine production by endothelial, epithelial cells and macrophages, although the precise mechanisms of inflammatory activation induced by VILI-relevant cyclic stretch remain poorly understood. We show that exposure of human pulmonary endothelial cells (EC) to chronic cyclic stretch at 18% linear distension (18% CS), but not at physiologically relevant 5% CS, induces "EC activated phenotype", which was characterized by time-dependent increase in ICAM1 and VCAM1 expression. 18% CS increased in a time-dependent fashion the release of soluble ICAM1 (sICAM1) and IL-8. Investigation of potential signaling mechanisms of CS-induced EC inflammatory activation showed that 18% CS, but not 5% CS induced time-dependent upregulation of VEGF receptor 2 (VEGFR2). Both, CS-induced VEGFR2 expression and tyrosine phosphorylation was abrogated by co-treatment with ROS inhibitor, N-acetyl cysteine. Molecular inhibition of VEGFR2 expression by gene-specific siRNA or treatment with VEGFR2 pharmacologic inhibitor SU-1498 attenuated CS-induced ICAM1 and VCAM1 expression and sICAM1 release. Chronic EC preconditioning at 18% CS augmented EC inflammation and barrier disruptive response induced by proinflammatory cytokine TNFα. This effect was attenuated by siRNA-induced VEGFR2 knockdown. This study demonstrates for the first time a VEGFR2-dependent mechanism of EC inflammatory activation induced by pathologic CS. We conclude that, despite the recognized role of VEGF as a pro-survival and angiogenic factor, excessive activation of VEGFR2 signaling by high tidal volume lung mechanical ventilation may contribute to ventilator-induced (biotrauma) lung inflammation and barrier dysfunction by augmenting cell response to VILI-associated inflammatory mediators.
- lung endothelium
- cyclic stretch
- Copyright © 2015, American Journal of Physiology - Lung Cellular and Molecular Physiology