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Purpose . Neutrophil-dominated airway inflammation is a key feature of progressive lung damage in cystic fibrosis (CF). Thus, reducing airway inflammation is a major goal to prevent lung damage in CF. However, current anti-inflammatory drugs have shown several limits. PI3K γ  plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3K γ  on airway inflammation and structural lung damage in a mouse model of CF lung disease.  Methods .  β ENaC overexpressing mice ( β ENaC-Tg) were backcrossed with PI3K γ -deficient (PI3K γ   KO ) mice. Tissue damage was assessed by histology and morphometry and inflammatory cell number was evaluated in bronchoalveolar lavage fluid (BALF). Furthermore, we assessed the effect of a specific PI3K γ  inhibitor (AS-605240) on inflammatory cell number in BALF.  Results . Genetic deletion of PI3K γ  decreased neutrophil numbers in BALF of PI3K γ   KO / β ENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3K γ  inhibitor AS-605240 decreased the number of neutrophils in BALF of  β ENaC-Tg mice, reproducing the effect observed with genetic deletion of the enzyme.  Conclusions . These results demonstrate the biological efficacy of both genetic deletion and pharmacological inhibition of PI3K γ  in reducing chronic neutrophilic inflammation in CF-like lung disease  in vivo .

mediators of inflammation

Genetic Deletion and Pharmacological Inhibition of PI3K<b><i>γ</i></b>Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

Genetic Deletion and Pharmacological Inhibition of PI3KγReduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease