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Mediators of Inflammation
Volume 2015, Article ID 545417, 10 pages
Research Article

Genetic Deletion and Pharmacological Inhibition of PI3Kγ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease

1Department of Clinical and Biological Sciences, University of Torino, A.O.U. S.Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043 Turin, Italy
2Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy
3Department of Physiopathology, Experimental Medicine, and Public Health, University of Siena, 53100 Siena, Italy
4Department of Neuroscience, University of Torino, 10126 Turin, Italy
5Institute of Medical Microbiology and Hygiene, University of Tübingen, 72074 Tübingen, Germany
6Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, Germany

Received 14 November 2014; Accepted 20 January 2015

Academic Editor: Anshu Agrawal

Copyright © 2015 Maria Galluzzo et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


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. PI3Kγ plays a pivotal role in leukocyte recruitment and activation; in the present study we determined the effects of genetic deletion and pharmacologic inhibition of PI3Kγ on airway inflammation and structural lung damage in a mouse model of CF lung disease. Methods. βENaC overexpressing mice (βENaC-Tg) were backcrossed with PI3Kγ-deficient () 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 PI3Kγ inhibitor (AS-605240) on inflammatory cell number in BALF. Results. Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of /βENaC-Tg mice, and this was associated with reduced emphysematous changes. Treatment with the PI3Kγ inhibitor AS-605240 decreased the number of neutrophils in BALF of βENaC-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 PI3Kγ in reducing chronic neutrophilic inflammation in CF-like lung disease in vivo.