title: Rapamycin reduces high-amplitude, mechanical stretch-induced apoptosis in pulmonary microvascular endothelial cells.
abstract: Alveolar epithelial and endothelial cell death caused by mechanical over-distension is likely to contribute to ventilator-induced lung injury (VILI). Consequently, the search for cytoprotective interventions is of interest. We investigated the effect of the mTOR inhibitor rapamycin on human pulmonary microvascular endothelial cell (HMVEC-L) viability in a model of high-amplitude mechanical stretch. Cyclic mechanical stretch (30% increase in membrane surface area, cycling frequency 40/min), employed for 24 h induced apoptosis in HMVEC-L. This effect was reduced by rapamycin treatment. Focusing on possible mechanisms of action we demonstrated that the stretch-induced reduction in the anti-apoptotic messenger pAkt could be restored by rapamycin treatment. Furthermore, we observed rapamycin-induced modifications in the HMVEC-L actin cytoskeleton architecture and global cellular f-actin content which functionally resulted in an increased global cellular mechanical stability - as indicated by an increased HMVEC-L osmomechanical resistance - thereby possibly desensitizing HMVEC-L to mechanical stimulation. According to the data from the present study, rapamycin represents a promising cytoprotective agent under mechanically challenging conditions such as mechanical ventilation.
authors.affiliation: Department of Respiratory Medicine, University of Leipzig, Johannisallee 32, 04103 Leipzig, Germany. uwe.raaz@web.de
authors.forename: Uwe
authors.initials: U
authors.lastname: Raaz
authors.forename: Hartmut
authors.initials: H
authors.lastname: Kuhn
authors.forename: Hubert
authors.initials: H
authors.lastname: Wirtz
authors.forename: Stefan
authors.initials: S
authors.lastname: Hammerschmidt