Autor(es):
Campa, Carlo C. ; Silva, Rangel L. ; Margaria, Jean P. ; Piral, 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 ; Bello, Bello ; 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
Data: 2019
Origem: Oasisbr
Assunto(s): Asma; Asthma; Fibrose; Fibrosis
Descrição
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.
