title: Genetic Deletion and Pharmacological Inhibition of PI3K γ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease.
abstract: OBJECTIVE
  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 (PI3Kγ (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 PI3Kγ inhibitor (AS-605240) on inflammatory cell number in BALF.
  
  
  RESULTS
  Genetic deletion of PI3Kγ decreased neutrophil numbers in BALF of PI3Kγ (KO)/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.
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, A.O.U. S.Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043 Turin, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Galluzzo
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Ciraolo
authors.affiliation: Department of Physiopathology, Experimental Medicine, and Public Health, University of Siena, 53100 Siena, Italy.
authors.forename: Monica
authors.initials: M
authors.lastname: Lucattelli
authors.affiliation: Department of Neuroscience, University of Torino, 10126 Turin, Italy.
authors.forename: Eriola
authors.initials: E
authors.lastname: Hoxha
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Ulrich
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Carlo Cosimo
authors.initials: CC
authors.lastname: Campa
authors.affiliation: Department of Physiopathology, Experimental Medicine, and Public Health, University of Siena, 53100 Siena, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Lungarella
authors.affiliation: Institute of Medical Microbiology and Hygiene, University of Tübingen, 72074 Tübingen, Germany.
authors.forename: Gerd
authors.initials: G
authors.lastname: Doring
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Zhou-Suckow
authors.affiliation: Department of Translational Pulmonology, Translational Lung Research Center Heidelberg (TLRC), German Center for Lung Research (DZL), University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Marcus
authors.initials: M
authors.lastname: Mall
authors.affiliation: Department of Molecular Biotechnology and Health Sciences, Center for Molecular Biotechnology, University of Torino, Via Nizza 52, 10126 Turin, Italy.
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.affiliation: Department of Clinical and Biological Sciences, University of Torino, A.O.U. S.Luigi Gonzaga, Regione Gonzole 10, Orbassano, 10043 Turin, Italy.
authors.forename: Virginia
authors.initials: V
authors.lastname: De Rose
mesh_terms: D000818:Animals; D058544:Class Ib Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000502:physiology*; D003550:Cystic Fibrosis / Q000150:complications / Q000473:pathology / Q000628:therapy*; D053503:Epithelial Sodium Channels / Q000502:physiology; D017353:Gene Deletion; D007249:Inflammation / Q000517:prevention & control*; D008168:Lung / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration; D000081082:Phosphoinositide-3 Kinase Inhibitors
chemical_list: D053503:Epithelial Sodium Channels; D000081082:Phosphoinositide-3 Kinase Inhibitors; D058544:Class Ib Phosphatidylinositol 3-Kinase; C546764:Pik3cg protein, mouse