Abstract：
Cystic fibrosis is a genetic disorder characterized by recurrent airway infections, inflammation, impaired mucociliary clearance and progressive decline in lung function. The disease may start in the small airways; however, this is difficult to prove due to limited accessibility of the small airways with the current single photon mucociliary clearance assay. Here, we developed a dynamic positron emission tomography assay with high spatial and temporal resolution. We tested that mucociliary clearance is abnormal in the small airways of newborn cystic fibrosis pigs. Clearance of [68Ga] tagged macro-aggregated albumin from small airways started immediately after delivery and continued for the duration of the study. Initial clearance was fast but slowed down few minutes after delivery. Cystic fibrosis pig small airways cleared significantly less than non-CF pig small airways (non-CF 25.1±3.1% vs. CF 14.6±0.1%). Stimulation of the cystic fibrosis airways with the purinergic secretagogue UTP further impaired clearance (non-CF with UTP 20.9±0.3% vs. CF with UTP 13.0±1.8%). None of the cystic fibrosis pig treated with UTP (N = 6) cleared more than 20% of the delivered dose. These data indicate that mucociliary clearance in the small airways is fast and can easily be missed if the assay is not sensitive enough. The data also indicate that mucociliary clearance is impaired in the small airways of cystic fibrosis pigs. This defect is exacerbated by stimulation of mucus secretions with purinergic agonists.
摘要：
囊性纤维化是一种以反复气道感染为特征的遗传性疾病,炎症,粘液纤毛清除受损和肺功能进行性下降。这种疾病可能始于小气道；然而，这是很难证明，由于有限的小气道的可及性与目前的单光子粘膜纤毛清除试验。这里,我们开发了一种具有高空间和时间分辨率的动态正电子发射断层扫描分析。我们测试了新生囊性纤维化猪的小气道中的粘膜纤毛清除异常。[68Ga]标记的宏观聚集的白蛋白在递送后立即从小气道中清除,并持续研究期间。最初的清除速度很快，但在交货后几分钟就减慢了。囊性纤维化猪小气道清除率明显低于非CF猪小气道（非CF25.1±3.1％vs.CF14.6±0.1%）。用嘌呤能促分泌素UTP刺激囊性纤维化气道进一步损害清除率（UTP的非CF为20.9±0.3％vs.CF与UTP13.0±1.8%）。用UTP(N=6)处理的囊性纤维化猪没有清除超过20%的递送剂量。这些数据表明,小气道中的粘膜纤毛清除是快速的,并且如果测定不够灵敏,则很容易被错过。数据还表明，囊性纤维化猪的小气道中的粘膜纤毛清除受损。嘌呤能激动剂刺激粘液分泌物会加剧这种缺陷。
