PI3K-γ inhibition ameliorates acute lung injury through regulation of IκBα/NF-κB pathway and innate immune responses

Background Acute lung injury (ALI) is a devastating disorder of the lung by various causes and its cardinal features are tissue inflammation, pulmonary edema, low lung compliance, and widespread capillary leakage. Among phosphoinositide 3-kinases (PI3Ks), PI3K-γ isoform has been shown to play an important role in a number of immune/inflammatory responses. Methods We investigated the role of PI3K-γ and its molecular basis in lipopolysaccharide (LPS)-induced ALI using a selective inhibitor for PI3K-γ, AS 605240, and LPS-treated C57BL/6 mice. Results Treatment of mice with LPS showed an increase of lung inflammation and vascular leakage. Production of reactive oxygen species (ROS), interleukin (IL)-1β, tumor necrosis factor-α, and IL-4, adhesion molecule, and vascular endothelial growth factor (VEGF) was also increased. Administration of AS 605240 to LPS-treated mice markedly reduced the pathophysiological features of ALI and the increased production of ROS, cytokines, adhesion molecule, and VEGF in the lung. Our results also showed that treatment of mice with LPS activates nuclear factor-κB (NF-κB) and degradation of inhibitory κBα (IκBα) through PI3K-γ. Additionally, infiltration of dendritic cells (DCs) and expression of toll-like receptor 4 (TLR4) were significantly increased in the lung of LPS-treated mice, and inhibition of PI3K-γ reduced the infiltration of DCs and TLR4 expression in the lung. Conclusions These results indicate that PI3K-γ is critically involved in LPS-induced ALI by regulating IκBα/NF-κB pathway and innate immune responses. Based on our data, we suggest that PI3K-γ isoform is a promising target for the treatment of ALI.