title: Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema.
abstract: BACKGROUND
  Ventilator-induced lung injury (VILI) occurs in part by increased vascular permeability and impaired alveolar fluid clearance. Phosphoinositide 3-kinase gamma (PI3Kγ) is activated by mechanical stress, induces nitric oxide (NO) production, and participates in cyclic adenosine monophosphate (cAMP) hydrolysis, each of which contributes to alveolar edema. We hypothesized that lungs lacking PI3Kγ or treated with PI3Kγ inhibitors would be protected from ventilation-induced alveolar edema and lung injury.
  
  
  METHODS
  Using an isolated and perfused lung model, wild-type (WT) and PI3Kγ-knockout (KO) mice underwent negative-pressure cycled ventilation at either -25 cmH₂O and 0 cmH₂O positive end-expiratory pressure (PEEP) (HIGH STRESS) or -10 cmH₂O and -3 cmH₂O PEEP (LOW STRESS).
  
  
  RESULTS
  Compared with WT, PI3Kγ-knockout mice lungs were partially protected from VILI-induced derangement of respiratory mechanics (lung elastance) and edema formation [bronchoalveolar lavage (BAL) protein concentration, wet/dry ratio, and lung histology]. In PI3Kγ-knockout mice, VILI induced significantly less phosphorylation of protein kinase B (Akt), endothelial nitric oxide synthase (eNOS), production of nitrate and nitrotyrosine, as well as hydrolysis of cAMP, compared with wild-type animals. PI3Kγ wild-type lungs treated with AS605240, an inhibitor of PI3Kγ kinase activity, in combination with enoximone, an inhibitor of phosphodiesterase-3 (PDE3)-induced cAMP hydrolysis, were protected from VILI at levels comparable to knockout lungs.
  
  
  CONCLUSIONS
  Phosphoinositide 3-kinase gamma in resident lung cells mediates part of the alveolar edema induced by high-stress ventilation. This injury is mediated via altered Akt, eNOS, NO, and/or cAMP signaling. Anti-PI3Kγ therapy aimed at resident lung cells represents a potential pharmacologic target to mitigate VILI.
authors: Department of Anesthesia and Critical Care, Ospedale S. Giovanni Battista-Molinette, University of Torino, Corso Dogliotti 14, 10126, Turin, Italy.
authors: Vito
authors: V
authors: Fanelli
authors: Valeria
authors: V
authors: Puntorieri
authors: Barbara
authors: B
authors: Assenzio
authors: Erica L
authors: EL
authors: Martin
authors: Vincenzo
authors: V
authors: Elia
authors: Martino
authors: M
authors: Bosco
authors: Luisa
authors: L
authors: Delsedime
authors: Lorenzo
authors: L
authors: Del Sorbo
authors: Andrea
authors: A
authors: Ferrari
authors: Stefano
authors: S
authors: Italiano
authors: Alessandra
authors: A
authors: Ghigo
authors: Arthur S
authors: AS
authors: Slutsky
authors: Emilio
authors: E
authors: Hirsch
authors: V Marco
authors: VM
authors: Ranieri
mesh_terms: D000818:Animals; D002199:Capillary Permeability; D004487:Edema / Q000209:etiology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000009:adverse effects* / Q000378:metabolism; D015656:Respiratory Mechanics; D055397:Ventilator-Induced Lung Injury / Q000209:etiology* / Q000503:physiopathology
chemical_list: D019869:Phosphatidylinositol 3-Kinases