Loss of integrity of epithelial and endothelial cell monolayers has been suggested to play an important role in the ventilatorinduced disruption of the alveolar-capillary barrier. One of the crucial systems regulating vascular cell integrity is the angiopoietin -Tie2 system. Clarifying the role of the Ang-Tie2 system in the development of lung injury has therefore become a topic of great interest. However, to date little is known about the interaction of mechanical stretch with the Ang-Tie2 system. It has been recognized that Ang-1 serves as a Tie2 receptor agonist by phosphorylating Tie2 on tyrosine residues. Ang-12mediated Tie2 signaling is required to maintain cellular integrity and quiescence of the endothelial barrier. The antagonist Ang-2 is known to downregulate Tie2 signaling, thereby preparing vascular endothelial cells for enhanced responsiveness to factors that cause destabilization of the endothelial barrier. However, there is also conflicting evidence that Ang-2 may cause Tie2 activation in stressed endothelial cells. In a murine model of endotoxin-induced acute lung injury, Karmpaliotis et al. described that vascular permeability and pulmonary edema were accompanied by enhanced vascular endothelial growth factor and reduced Ang-1 levels in lung tissue. The same authors proposed that changes in the balance between VEGF and Ang-1 might contribute to the pathophysiology of ALI. Protective effects of Ang-1 treatment have been shown before in experimental models of endotoxin-induced ALI. Mei et al. demonstrated that treatment with Ang-1 attenuated vascular leakage, granulocyte infiltration and DAPT pro-inflammatory cytokine expression in lungs of endotoxin-exposed mice. Consequently, the AngTie2 system has been proposed as a possible therapeutic target in pulmonary diseases like ALI and its most severe form, the acute respiratory distress syndrome . Vascular leakage and pulmonary inflammation are important features of VILI. Therefore, we hypothesized that Ang-12Tie2 signaling plays a role in the development of VILI. In an attempt to better reflect the human setting, we applied a relatively mild model of VILI using clinically relevant ventilator settings thereby preventing shock, metabolic acidosis and substantial damage to lung architecture. The aim of present study was to investigate the influence of mechanical ventilation on the AngTie2 system in lungs of healthy adult mice. Furthermore, we examined whether treatment with Ang-1, a Tie2 receptor agonist, would protect ventilated mice against important hallmarks of VILI such as inflammation, vascular leakage and impaired gas exchange. In experimental studies, mechanical ventilation has been described to induce destabilization of the alveolar-capillary barrier thereby leading to enhanced pulmonary permeability and edema formation. Most models of VILI, however, applied very high inspiratory pressures or tidal volumes when compared to those used in the human setting.