Lack of phosphoinositide 3-kinase-gamma attenuates ventilator-induced lung injury.
OBJECTIVE
G protein-coupled receptors may up-regulate the inflammatory response elicited by ventilator-induced lung injury but also regulate cell survival via protein kinase B (Akt) and extracellular signal regulated kinases 1/2 (ERK1/2). The G protein-sensitive phosphoinositide-3-kinase gamma (PI3Kgamma) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3Kgamma on ventilator-induced lung injury.


METHODS
Prospective, randomized, experimental study.


METHODS
University animal research laboratory.


METHODS
Wild-type (PI3Kgamma), knock-out (PI3Kgamma ), and kinase-dead (PI3Kgamma) mice.


METHODS
Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3Kgamma, PI3Kgamma, and PI3Kgamma mice.


RESULTS
Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01). Inflammatory cytokines and IkBalpha phosphorylation with high stretch did not differ among PI3Kgamma, PI3Kgamma, and PI3Kgamma. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p < .01) in PI3Kgamma and PI3Kgamma than in PI3Kgamma. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3Kgamma mice whereas PI3Kgamma mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3Kgamma than in PI3Kgamma and PI3Kgamma (p < .01).


CONCLUSIONS
Silencing PI3Kgamma seems to attenuate functional and morphological consequences of ventilator-induced lung injury independently of inhibitory effects on cytokines release but through the enhancement of pulmonary apoptosis.
Lionetti
Vincenzo
V
Dipartimento di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista-Molinette, Università di Torino, Torino, Italy.
Lisi
Alberto
A
Patrucco
Enrico
E
De Giuli
Paolo
P
Milazzo
Maria Giovanna
MG
Ceci
Simone
S
Wymann
Matthias
M
Lena
Annalisa
A
Gremigni
Vittorio
V
Fanelli
Vito
V
Hirsch
Emilio
E
Ranieri
V Marco
VM
D000818:Animals; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D016207:Cytokines / Q000032:analysis / Q000378:metabolism*; D004195:Disease Models, Animal; D004797:Enzyme-Linked Immunosorbent Assay; D007150:Immunohistochemistry; D008168:Lung / Q000473:pathology; D008171:Lung Diseases / Q000201:enzymology* / Q000503:physiopathology; D055370:Lung Injury; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000378:metabolism*; D011897:Random Allocation; D012016:Reference Values; D012121:Respiration, Artificial / Q000009:adverse effects*; D012129:Respiratory Function Tests; D012131:Respiratory Insufficiency / Q000503:physiopathology*; D012680:Sensitivity and Specificity; D015854:Up-Regulation
D015415:Biomarkers; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases