1区 · 综合性期刊
ArticleOA
作者: Tron, Gian Cesare ; Grosa, Giorgio ; Reis, Diego C ; Teixeira, Mauro M ; Pirali, Tracey ; Copperi, Francesca ; Dalmarco, Eduardo M ; Alves-Filho, Jose Carlos ; Cassali, Geovanni D ; Medana, Claudio ; Campa, Carlo C ; Mattos, Matheus S ; Ciraolo, Elisa ; Dal Bello, Federica ; Aprile, Silvio ; Kraemer, Lucas R ; Silva, Rangel L ; Sala, Valentina ; Prado, Douglas Silva ; Hirsch, Emilio ; Lima-Júnior, Roberto C P ; Margaria, Jean P ; Russo, Remo C
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.