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Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis

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Item Type:Article
Title:Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
Creators Name:Campa, C.C., Silva, R.L., Margaria, J.P., Pirali, T., Mattos, M.S., Kraemer, L.R., Reis, D.C., Grosa, G., Copperi, F., Dalmarco, E.M., Lima-Júnior, R.C.P., Aprile, S., Sala, V., Dal Bello, F., Prado, D.S., Alves-Filho, J.C., Medana, C., Cassali, G.D., Tron, G.C., Teixeira, M.M., Ciraolo, E., Russo, R.C. and Hirsch, E.
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.
Keywords:Animal Disease Models, Asthma, Bleomycin, Enzyme Inhibitors, Inbred BALB C Mice, Inbred C57BL Mice, Inhalation Administration, Ovalbumin, Phosphatidylinositol 3-Kinases, Phosphorylation, Proto-Oncogene Proteins c-akt, Pulmonary Fibrosis, Animals, Mice
Source:Nature Communications
Publisher:Nature Publishing Group
Page Range:5232
Date:12 December 2018
Official Publication:https://doi.org/10.1038/s41467-018-07698-6
PubMed:View item in PubMed

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