Abstract：
Cystic fibrosis (CF) results in a reduction in the volume of airway surface liquid, increased accumulation of viscous mucus, persistent antibiotic-resistant lung infections that cause chronic inflammation, and a decline in lung function. More than 50% of adults with CF are chronically colonized by Pseudomonas aeruginosa (P. aeruginosa), the primary reason for morbidity and mortality in people with CF (pwCF). Although highly effective modulator therapy (HEMT) is an important part of disease management in CF, HEMT does not eliminate P. aeruginosa or lung inflammation. Thus, new treatments are required to reduce lung infection and inflammation in CF. In a previous in vitro study, we demonstrated that primary human bronchial epithelial cells (HBECs) secrete extracellular vesicles (EVs) that block the ability of P. aeruginosa to form biofilms by reducing the abundance of several proteins necessary for biofilm formation as well as enhancing the sensitivity of P. aeruginosa to β-lactam antibiotics. In this study, using a CF mouse model of P. aeruginosa infection, we demonstrate that intratracheal administration of EVs secreted by HBEC reduced P. aeruginosa lung burden and several proinflammatory cytokines including IFN-γ, TNF-α, and MIP-1β in bronchoalveolar lavage fluid (BALF), even in the absence of antibiotics. Moreover, EVs decreased neutrophils in BALF. Thus, EVs secreted by HBEC reduce the lung burden of P. aeruginosa, decrease inflammation, and reduce neutrophils in a CF mouse model. These results suggest that HBEC via the secretion of EVs may play an important role in the immune response to P. aeruginosa lung infection.NEW & NOTEWORTHY Our findings show that extracellular vesicles secreted by primary human bronchial epithelial cells significantly reduce Pseudomonas aeruginosa burden, inflammation, and weight loss in a cystic fibrosis mouse model of infection.
摘要：
囊性纤维化（CF）导致气道表面液体的体积减少，粘稠粘液的积累增加，导致慢性炎症和肺功能下降的持续性抗生素耐药肺部感染。超过50%的CF成人长期被铜绿假单胞菌定植(P.铜绿假单胞菌)，CF（pwCF）患者发病和死亡的主要原因。尽管高效的调质疗法（HEMT）是CF疾病管理的重要组成部分，HEMT不能消除铜绿假单胞菌或肺部炎症。因此，需要新的治疗方法来减少CF的肺部感染和炎症。在先前的体外研究中，我们证明了原代人支气管上皮细胞（HBEC）分泌细胞外囊泡（EV），通过减少生物膜形成所需的几种蛋白质的丰度来阻断铜绿假单胞菌形成生物膜的能力以及增强铜绿假单胞菌对β-内酰胺抗生素的敏感性。在使用铜绿假单胞菌感染的CF小鼠模型的这项研究中，我们证明了由HBEC分泌的EV的气管内给药减少了铜绿假单胞菌的肺负荷和几种促炎细胞因子，包括IFN-γ，TNF-α,和支气管肺泡液（BALF）中的MIP-1β，即使没有抗生素。此外，EV减少BALF中的中性粒细胞。因此，HBEC分泌的电动汽车可降低铜绿假单胞菌的肺负担，减少CF小鼠模型中的炎症和减少中性粒细胞。这些结果表明，HBEC通过分泌EV可能在铜绿假单胞菌肺部感染的免疫应答中起重要作用。
