Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs
To determine the role of phosphoinositide 3-OH kinase (PI3K) pathways in the acute vascular permeability increase associated with ventilator-induced lung injury, we ventilated isolated perfused lungs and intact C57BL/6 mice with low and high peak inflation pressures (PIP). In isolated lungs, filtration coefficients (Kf) increased significantly after ventilation at 30 cmH2O (high PIP) for successive periods of 15, 30 (4.1-fold), and 50 (5.4-fold) min. Pretreatment with 50 ÂµM of the PI3K inhibitor, LY-294002, or 20 ÂµMPP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas 10 ÂµM Akt inhibitor IV significantly augmented the increased Kf. There were no significant differences in Kf or lung wet-to-dry weight (W/D) ratios between groups ventilated with 9 cmH 2O PIP (low PIP), with or without inhibitor treatment. Total lung ÃŸ-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total ÃŸ-catenin by 86%. Ventilation of intact mice with 55 cmH2O PIP for up to 60 min also increased lung vascular permeability, indicated by increases in lung lavage albumin concentration and lung W/D ratios. In these lungs, tyrosine phosphorylation of ÃŸ-catenin and serine/threonine phosphorylation of Akt, glycogen synthase kinase 3ÃŸ (GSK3ÃŸ), and ERK1/2 increased significantly with peak effects at 60 min. Thus mechanical stress activation of PI3K and Src may increase lung vascular permeability through tyrosine phosphorylation, but simultaneous activation of the PI3K-Akt-GSK3ÃŸ pathway tends to limit this permeability response, possibly by preserving cellular ÃŸ-catenin. Copyright Â© 2007 the American Physiological Society.
American Journal of Physiology - Lung Cellular and Molecular Physiology
Miyahara, T.; Hamanaka, K.; Weber, D. S.; Drake, D. A.; Anghelescu, Mircea; and Parker, J. C., "Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs" (2007). PCOM Scholarly Papers. 1524.