Mouse models have been successfully used to investigate pathomechanisms of VILI [18-20]. The currently employed mouse model allowed us to analyze key features of VILI while avoiding detrimental lung injury due to high airway pressures, tidal volumes or respiration Ganetespib HSP (e.g. HSP90) inhibitor rates. Although a VT of 6 ml/kg is recommended for lung protective ventilation, we employed a VT of 12 ml/kg which allowed for limitation of respiratory rates in our model, an important independent trigger of VILI in mice [21]. Further lung stress and lung strain, generated by a VT of 12 ml/kg affecting healthy lungs in the current model may apply in ventilated areas of inhomogeneously injured lungs even under lung protective ventilation according to the baby lung concept of the inhomogeneous ARDS lung [22,23].

To further enhance clinical relevance, we prevented hemodynamic instability by fluid support and metabolic acidosis by adequate infusion of sodium bicarbonate. In summary, a mouse model was established for the current study, which evoked moderate lung injury by ventilation for a six-hour period.Microvascular leakage, a hallmark of VILI evokes lung edema, reduction of lung compliance, surfactant dysfunction, and finally deterioration of pulmonary gas exchange [4]. Statins prevented pulmonary hyperpermeability in ALI evoked by different stimuli, including endotoxin and ischemia/reperfusion [8-10]. Of note, simvastatin treatment also reduced VILI-associated pulmonary hyperpermeability and improved pulmonary gas exchange in the current study.

Different mechanisms of endothelial barrier protection by HMG-CoA reductase inhibitors have been reported, including inhibition of the RhoA/Rho kinase pathway with consecutive reduction of endothelial myosin light chain phosphorylation [24-26], stabilization of endothelial junctions by polymerization of cortical actin [25], as well as downregulation of endothelial caldesmon and upregulation of integrin ��4 expression in endothelial cells [25]. Although these mechanisms were not evaluated in detail in the current study, they may have been contributing to the observed improvement of barrier function in murine VILI. Notably, an additional way of endothelial cell protection by simvastatin has now been observed by electron microscopy. Simvastatin attenuated VILI-evoked cell swelling and loss of intracellular vesicle structures in lung endothelium, which are indicators of energy depletion and impaired cell metabolism.

Previous in vitro and in vivo studies linked cyclic stretch with apoptosis and necrosis of pulmonary epithelial cells [27,28]. In line with the works of Vaneker et al. this study provides ultrastructural in vivo evidence for lung Batimastat endothelial cell injury following ventilation with moderate tidal volumes [29]. The observed morphologic findings resemble alterations observed in capillary stress failure previously described by West et al.