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
in 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.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Neutrophil Infiltration
/
Cystic Fibrosis
/
Class Ib Phosphatidylinositol 3-Kinase
/
Inflammation
/
Lung
Limits:
Animals
Language:
En
Journal:
Mediators Inflamm
Journal subject:
BIOQUIMICA
/
PATOLOGIA
Year:
2015
Document type:
Article
Affiliation country:
Italia