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1 Physiology, University of South Alabama, Mobile, Alabama, United States; Center for Lung Biology, University of South Alabama, Mobile, Alabama, United States
2 Physiology, University of South Alabama, Mobile, Alabama, United States
* To whom correspondence should be addressed. E-mail: jparker{at}usouthal.edu.
To determine the role of phosphoinositide 3-OH kinase (PI3K) pathways in the acute vascular permeability increase associated with ventilator-induced lung injury (VILI), 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 min, 30 min (4.1-fold) and 50 min (5.4-fold). Pretreatment with 50 µM of the PI3K inhibitor, LY294002, or 20 µM PP2, a Src kinase inhibitor, significantly attenuated the increase in Kf, whereas, 10 µM of Akt inhibitor IV significantly augmented the increased Kf. There were no significant differences in Kf or lung wet to dry weight ratios (W/D) between groups ventilated with 9 cmH2O PIP (Low PIP) with our without inhibitor treatment. Total lung 
-catenin was unchanged in any Low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total -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 -catenin, and serine/threonine phosphorylation of Akt, GSK3 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-GSK3 pathway tends to limit this permeability response possibly by preserving cellular -catenin.
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