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 γ (PI3Kγ) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3Kγ on ventilator-induced lung injury.

Design:

Prospective, randomized, experimental study.

Setting:

University animal research laboratory.

Subjects:

Wild-type (PI3Kγ+/+), knock-out (PI3Kγ−/−), and kinase-dead (PI3Kγ KD/KD) mice.

Interventions:

Three ventilatory strategies (no stretch, low stretch, high stretch) were studied in an isolated, nonperfused model of acute lung injury (lung lavage) in PI3Kγ+/+, PI3Kγ−/−, and PI3Kγ KD/KD mice.

Measurements and Main Results:

Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3Kγ+/+ than in PI3Kγ−/− and PI3Kγ KD/KD (p<. 01). Inflammatory cytokines and IkBα phosphorylation with high stretch did not differ among PI3Kγ+/+, PI3Kγ−/−, and PI3Kγ KD/KD. Apoptotic index (terminal deoxynucleotidyl transferase-mediated biotin-dUTP nick-end labeling) and caspase-3 (immunohistochemistry) with high stretch were larger (p<. 01) in PI3Kγ−/− and PI3Kγ KD/KD than in PI3Kγ+/+. Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3Kγ−/− mice whereas PI3Kγ+/+ mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3Kγ+/+ than in PI3Kγ−/− and PI3Kγ KD/KD (p<. 01).

Conclusions:

Silencing PI3Kγ 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.