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 (K(f)) increased significantly after ventilation at 30 cmH(2)O (high PIP) for successive periods of 15, 30 (4.1-fold), and 50 (5.4-fold) min. Pretreatment with 50 microM of the PI3K inhibitor, LY-294002, or 20 microM PP2, a Src kinase inhibitor, significantly attenuated the increase in K(f), whereas 10 microM Akt inhibitor IV significantly augmented the increased K(f). There were no significant differences in K(f) or lung wet-to-dry weight (W/D) ratios between groups ventilated with 9 cmH(2)O PIP (low PIP), with or without inhibitor treatment. Total lung beta-catenin was unchanged in any low PIP isolated lung group, but Akt inhibition during high PIP ventilation significantly decreased total beta-catenin by 86%. Ventilation of intact mice with 55 cmH(2)O 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 beta-catenin and serine/threonine phosphorylation of Akt, glycogen synthase kinase 3beta (GSK3beta), 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-GSK3beta pathway tends to limit this permeability response, possibly by preserving cellular beta-catenin.
Miyahara
Takashige
T
Department of Physiology, University of South Alabama, Mobile, Alabama 36688, USA.
Hamanaka
Kazutoshi
K
Weber
David S
DS
Drake
Douglas A
DA
Anghelescu
Mircea
M
Parker
James C
JC
D000818:Animals; D002199:Capillary Permeability / Q000502:physiology*; D005374:Filtration; D066298:In Vitro Techniques; D008168:Lung / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009929:Organ Size / Q000187:drug effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D011312:Pressure; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D012123:Pulmonary Ventilation / Q000502:physiology*; D013997:Time Factors; D014655:Vascular Resistance / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism
D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D016392:Proto-Oncogene Proteins pp60(c-src); D051176:beta Catenin