title: Lack of phosphoinositide 3-kinase-gamma attenuates ventilator-induced lung injury.
abstract: 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.
authors.affiliation: Dipartimento di Anestesiologia e Rianimazione, Ospedale S. Giovanni Battista-Molinette, Università di Torino, Torino, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Lionetti
authors.forename: Alberto
authors.initials: A
authors.lastname: Lisi
authors.forename: Enrico
authors.initials: E
authors.lastname: Patrucco
authors.forename: Paolo
authors.initials: P
authors.lastname: De Giuli
authors.forename: Maria Giovanna
authors.initials: MG
authors.lastname: Milazzo
authors.forename: Simone
authors.initials: S
authors.lastname: Ceci
authors.forename: Matthias
authors.initials: M
authors.lastname: Wymann
authors.forename: Annalisa
authors.initials: A
authors.lastname: Lena
authors.forename: Vittorio
authors.initials: V
authors.lastname: Gremigni
authors.forename: Vito
authors.initials: V
authors.lastname: Fanelli
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: V Marco
authors.initials: VM
authors.lastname: Ranieri
mesh_terms: 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
chemical_list: D015415:Biomarkers; D016207:Cytokines; D019869:Phosphatidylinositol 3-Kinases