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Title in Portuguese: Inhalation of the prodrug PI3K inhibitor CL27cimproves lung function in asthma andfibrosis
Author: 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
Keywords: Asma
Issue Date: Dec-2018
Publisher: Nature Communications
Citation: CAMPA, Carlo C. et al. Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis. Nature Communications, v. 12, n. 5232, p. 1-16, dec. 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 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.
metadata.dc.type: Artigo
ISSN: 2041-1723
Appears in Collections:PPGF - Artigos publicados em revistas científica

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