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*
Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Health Sciences Center, Denver, CO 80262; and
Amgen Institute, Ontario Cancer Institute, and Departments of Medical Biophysics and Immunology, University of Toronto, Toronto, Ontario, Canada
Activated neutrophils contribute to the development and severity of
acute lung injury (ALI). Phosphoinositide 3-kinases (PI3-K) and the
downstream serine/threonine kinase Akt/protein kinase B have a central
role in modulating neutrophil function, including respiratory burst,
chemotaxis, and apoptosis. In the present study, we found that exposure
of neutrophils to endotoxin resulted in phosphorylation of Akt,
activation of NF-
B, and expression of the proinflammatory cytokines
IL-1
and TNF-
through PI3-K-dependent pathways. In vivo,
endotoxin administration to mice resulted in activation of PI3-K and
Akt in neutrophils that accumulated in the lungs. The severity of
endotoxemia-induced ALI was significantly diminished in mice lacking
the p110
catalytic subunit of PI3-K. In PI3-K-/-
mice, lung edema, neutrophil recruitment, nuclear translocation of
NF-B, and pulmonary levels of IL-1 and TNF- were significantly
lower after endotoxemia as compared with PI3-K+/+
controls. Among neutrophils that did accumulate in the lungs of the
PI3-K-/- mice after endotoxin administration,
activation of NF-B and expression of proinflammatory cytokines was
diminished compared with levels present in lung neutrophils from
PI3-K+/+ mice. These results show that PI3-K, and
particularly PI3-K, occupies a central position in regulating
endotoxin-induced neutrophil activation, including that involved in
ALI.
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