Involvement of phosphoinositide 3-kinases in neutrophil activation and thedevelopment of acute lung injury

Activated neutrophils contribute to the development and severity of acute l ung injury (ALI). Phosphoinositide 3-kinases (PI3-K) and the downstream ser ine/threonine kinase Akt/protein kinase B have a central role in modulating neutrophil function, including respiratory burst, chemotaxis, and apoptosi s. In the present study, we found that exposure of neutrophils to endotoxin resulted in phosphorylation. of Akt, activation of NF-kappaB and expressio n of the proinflammatory cytokines IL-1 beta and TNF-a through PI3-K-depend ent pathways. In vivo, endotoxin administration to mice resulted in activat ion of PI3-K and Akt in neutrophils that accumulated in the lungs. The seve rity of endotoxemia-induced ALI was significantly diminished in mice lackin g the p110 gamma catalytic subunit of PI3-K. In PI3-K gamma (-/-) mice, lun g edema, neutrophil recruitment, nuclear translocation of NF-kappaB and pul monary levels of IL-1 beta and TNF-alpha were significantly lower after end otoxemia as compared with PI3-K gamma (+/+) controls. Among neutrophils tha t did accumulate in the lungs of the PI3-K gamma (-/-) mice after endotoxin administration, activation of NF-kappaB and expression of proinflammatory cytokines was diminished compared with levels present in lung neutrophils f rom PI3-K gamma (+/+) mice. These results show that PI3-K, and particularly PI3-K gamma, occupies a central position in regulating endotoxin-induced n eutrophil activation, including that involved in ALI.