Phosphoinositide 3-kinase, Src, and Akt modulate acute ventilation-induced vascular permeability increases in mouse lungs

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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 µM of the PI3K inhibitor, LY-294002, or 20 µMPP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas 10 µM 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 ß-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total ß-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 ß-catenin and serine/threonine phosphorylation of Akt, glycogen synthase kinase 3ß (GSK3ß), 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-GSK3ß pathway tends to limit this permeability response, possibly by preserving cellular ß-catenin. Copyright © 2007 the American Physiological Society.

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American Journal of Physiology - Lung Cellular and Molecular Physiology





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This article was published in American Journal of Physiology - Lung Cellular and Molecular Physiology, Volume 293, Issue 1, Pages L11-L21.

The published version is available at http://dx.doi.org/10.1152/ajplung.00279.2005.

Copyright © 2007.

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