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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
Nature communications, 12/2018, Volume: 9, Issue: 1Journal Article
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.
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