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 gamma (PI3K gamma) regulates several cellular functions including inflammation and cell survival. We explored the role of PI3K gamma on ventilator-induced lung injury. Design: Prospective, randomized, experimental study. Setting: University animal research laboratory. Subjects: Wild-type (PI3K gamma(+/+)), knock-out (PI3K gamma(-/-)), and kinase-dead (PI3K gamma(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 PI3K gamma(+/+), pI3K gamma(-/-), and PI3K gamma(KD/KD) mice. Measurements and Main Results: Reduction in lung compliance, hyaline membrane formation, and epithelial detachment with high stretch were more pronounced in PI3K gamma(+/+) than in PI3K gamma(-/-) and PI3K gamma(KD/KD) (p < .01). Inflammatory cytokines and IkB alpha phosphorylation with high stretch did not differ among PI3K gamma(+/+), PI3K gamma(-/-), and PI3K gamma(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 PI3K gamma(-/-) and PI3K gamma(KD/KD) than in PI3K gamma(+/+). Electron microscopy showed that high stretch caused apoptotic changes in alveolar cells of PI3K gamma(-/-) mice whereas PI3K gamma(+/+) mice showed necrosis. Phosphorylation of Akt and ERK1/2 with high stretch was more pronounced in PI3K gamma(+/+) than in PI3K gamma(-/-) and PI3K gamma(KD/KD) (p < .01). Conclusions: Silencing PI3K gamma 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.