Lack of phosphoinositide 3-kinase-γ 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 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.