Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
Inhalation of the prodrug PI3K inhibitor CL27c improves lung function in asthma and fibrosis
复制标题
DOI：
10.1038/s41467-018-07698-6
复制
发表时间：
2018-12-12
影响因子：
16.6
通讯作者：
Hirsch, Emilio
中科院分区：
文献类型：
--
作者：
Campa, Carlo C.;Silva, Rangel L.;Hirsch, Emilio
PI3K激活在肺部炎症的发展和组织重塑中起着核心作用。因此，PI3K抑制剂可能为治疗难以消退的肺部炎症提供一种更好的治疗机会，但其作用受到非预期的靶向全身毒性的限制。在此我们介绍CL27c，一种设计用于局部治疗的前药泛PI3K抑制剂，并研究吸入CL27c在哮喘和肺纤维化中是否有效。吸入CL27c的小鼠肺部胰岛素诱导的Akt磷酸化降低，但其他组织无变化，血糖也未升高，这与局部作用相符。在急性或糖皮质激素抵抗的中性粒细胞性哮喘小鼠模型中，吸入CL27c可减轻炎症并改善肺功能。最后，在治疗环境中给予吸入CL27c可防止博来霉素诱导的肺纤维化，最终显著提高生存率。因此，局部给予泛PI3K抑制剂前药可减少靶向全身副作用，但能有效治疗哮喘和不可逆的肺纤维化。
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.