Pulmonary-derived phosphoinositide 3-kinase gamma (PI3Kγ) contributes to ventilator-induced lung injury and edema.
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.
Fanelli
Vito
V
Department of Anesthesia and Critical Care, Ospedale S. Giovanni Battista-Molinette, University of Torino, Corso Dogliotti 14, 10126, Turin, Italy.
Puntorieri
Valeria
V
Assenzio
Barbara
B
Martin
Erica L
EL
Elia
Vincenzo
V
Bosco
Martino
M
Delsedime
Luisa
L
Del Sorbo
Lorenzo
L
Ferrari
Andrea
A
Italiano
Stefano
S
Ghigo
Alessandra
A
Slutsky
Arthur S
AS
Hirsch
Emilio
E
Ranieri
V Marco
VM
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
D019869:Phosphatidylinositol 3-Kinases