Back to Search
Start Over
Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis.
- Source :
-
Nature communications [Nat Commun] 2018 Dec 12; Vol. 9 (1), pp. 5232. Date of Electronic Publication: 2018 Dec 12. - Publication Year :
- 2018
-
Abstract
- PI3K activation plays a central role in the development of pulmonary inflammation and tissue remodeling. PI3K inhibitors may thus offer an improved therapeutic opportunity to treat non-resolving lung inflammation but their action is limited by unwanted on-target systemic toxicity. Here we present CL27c, a prodrug pan-PI3K inhibitor designed for local therapy, and investigate whether inhaled CL27c is effective in asthma and pulmonary fibrosis. Mice inhaling CL27c show reduced insulin-evoked Akt phosphorylation in lungs, but no change in other tissues and no increase in blood glycaemia, in line with a local action. In murine models of acute or glucocorticoid-resistant neutrophilic asthma, inhaled CL27c reduces inflammation and improves lung function. Finally, inhaled CL27c administered in a therapeutic setting protects from bleomycin-induced lung fibrosis, ultimately leading to significantly improved survival. Therefore, local delivery of a pan-PI3K inhibitor prodrug reduces systemic on-target side effects but effectively treats asthma and irreversible pulmonary fibrosis.
- Subjects :
- Administration, Inhalation
Animals
Asthma chemically induced
Asthma pathology
Benzene Derivatives administration & dosage
Bleomycin toxicity
Disease Models, Animal
Enzyme Inhibitors administration & dosage
Esters administration & dosage
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Ovalbumin toxicity
Phosphorylation drug effects
Proto-Oncogene Proteins c-akt metabolism
Pulmonary Fibrosis chemically induced
Pulmonary Fibrosis pathology
Asthma drug therapy
Benzene Derivatives therapeutic use
Enzyme Inhibitors therapeutic use
Esters therapeutic use
Phosphoinositide-3 Kinase Inhibitors
Pulmonary Fibrosis drug therapy
Subjects
Details
- Language :
- English
- ISSN :
- 2041-1723
- Volume :
- 9
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Nature communications
- Publication Type :
- Academic Journal
- Accession number :
- 30542075
- Full Text :
- https://doi.org/10.1038/s41467-018-07698-6