Genetic Deletion and Pharmacological Inhibition of PI3K γ Reduces Neutrophilic Airway Inflammation and Lung Damage in Mice with Cystic Fibrosis-Like Lung Disease.
Mediators Inflamm
; 2015: 545417, 2015.
Article
em En
| MEDLINE
| ID: mdl-26185363
ABSTRACT
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:
ßENaC overexpressing mice (ßENaC-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)/ßENaC-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 ßENaC-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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Infiltração de Neutrófilos
/
Fibrose Cística
/
Classe Ib de Fosfatidilinositol 3-Quinase
/
Inflamação
/
Pulmão
Limite:
Animals
Idioma:
En
Revista:
Mediators Inflamm
Assunto da revista:
BIOQUIMICA
/
PATOLOGIA
Ano de publicação:
2015
Tipo de documento:
Article
País de afiliação:
Itália