Inhibition of phosphoinositide 3 kinase delta attenuates allergic airway inflammation in mice

Abstract

Phosphoinositide 3‐kinase p110δ (PI3Kδ) plays a pivotal role in the recruitment and activation of inflammatory cells. The role of PI3Kδ in a mouse model of cockroach antigen (CRA)‐induced acute allergic airway inflammation was investigated using IC87114, a selective PI3Kδ inhibitor. BALB/c mice exposed to CRA developed airway eosinophilia associated with increased expression of IL‐2, IL‐17, IFNγ, IL‐4 and IL‐5 in lung tissue as well as of pro‐inflammatory chemokines eotaxin‐1 and MCP‐1 in bronchoalveolar lavage fluid (BALF) and lung tissue. Further, these mice developed airway hyperresponsiveness (AHR) to inhaled methacholine. Oral administration of IC87114 significantly attenuated CRA‐induced influx of inflammatory cells in the BALF (eosinophils and macrophages) and lung tissue and suppressed CRA‐induced AHR. Moreover, levels of IL‐2, IL‐17, IFNγ, IL‐4, and IL‐5 in lung tissue and of eotaxin‐1 and MCP‐1 in BALF as well as lung tissue were substantially reduced. Treatment of human eosinophils with IC87114 significantly inhibited eosinophil rolling on human umbilical vein endothelial cells as well as VCAM‐1 in vitro. Overall, these findings implicate that inhibition of the PI3Kδ may have therapeutic potential for the treatment of allergic airway inflammation. Supported by National Institutes of Health grants HL0793041 and AI35796.