Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
Articolo
Data di Pubblicazione:
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 nonresolving 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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
Administration, Inhalation; Animals; Asthma; Bleomycin; Disease Models, Animal; Enzyme Inhibitors; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Ovalbumin; Phosphatidylinositol 3-Kinases; Phosphorylation; Proto-Oncogene Proteins c-akt; Pulmonary Fibrosis; Chemistry (all); Biochemistry, Genetics and Molecular Biology (all); Physics and Astronomy (all)
Elenco autori:
Campa, Carlo C.; Silva, Rangel L.; Margaria, Jean P.; Pirali, Tracey; Mattos, Matheus S.; Kraemer, Lucas R.; Reis, Diego C.; Grosa, Giorgio; Copperi, Francesca; Dalmarco, Eduardo M.; Lima-Júnior, Roberto C. P.; Aprile, Silvio; Sala, Valentina; Dal Bello, Federica; Prado, Douglas Silva; Alves-Filho, Jose Carlos; Medana, Claudio; Cassali, Geovanni D.; Tron, Gian Cesare; Teixeira, Mauro M.; Ciraolo, Elisa; Russo, Remo C.; Hirsch, Emilio
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