Effects of phosphoinositide-3-kinase inhibitors on steroid-insensitive airway inflammation in poly(I:C) and allergen challenged mice

Viral infections induce exacerbations in asthmatic patients with increased airway inflammation that is corticosteroid-insensitive. The aim of this study was to evaluate the effects of phosphoinositide-3-kinase (PI3K) inhibitors on airway inflammation in induced by the viral mimic poly(I:C) in combination with ovalbumin in sensitized mice. A/J male mice were sensitized and challenged by OVA. Then poly(I:C) was given intranasally for 3 days, and AS604850 (AS; PI3Kγ inhibitor), IC87114 (IC; PI3Kδ inhibitor) and/or fluticasone propionate (FP, a corticosteroid) were administered intranasally 2h before each poly(I:C) exposure. Bronchoalveolar lavage fluid (BALF) was collected at 24h after the last poly(I:C) exposure. Macrophages, neutrophils and eosinophils in BALF were quantified by FACS analysis. The levels of CXCL1 and TNF-α in BALF were determined using a ELISA kit. Poly(I:C) exposure caused a significant increase in BALF macrophages, neutrophils, eosinophils, CXCL1 and TNF-α, which was not inhibited by FP (0.05 mg/ml). Neither AS (4.0 mg/ml) nor IC (4.0 mg/ml) alone inhibited airway inflammation, while the combination of IC and FP demonstrated greater inhibition on the inflammation in poly(I:C) and OVA-exposed mice. In contrast, the combination of AS and FP did not show anti-inflammatory activity. These data suggest that PI3Kδ inhibitor combined with a corticosteroid offers potential treatment for corticosteroid insensitive airway inflammation during viral infections.