1 Department of Anatomy & Cell Biology.
2 Department of Medicine.
Am J Respir Crit Care Med. 2018 May 15;197(10):1308-1318. doi: 10.1164/rccm.201708-1616OC.
Classical interpretation of cystic fibrosis (CF) lung disease pathogenesis suggests that infection initiates disease progression, leading to an exuberant inflammatory response, excessive mucus, and ultimately bronchiectasis. Although symptomatic antibiotic treatment controls lung infections early in disease, lifelong bacterial residence typically ensues. Processes that control the establishment of persistent bacteria in the CF lung, and the contribution of noninfectious components to disease pathogenesis, are poorly understood.
To evaluate whether continuous antibiotic therapy protects the CF lung from disease using a ferret model that rapidly acquires lethal bacterial lung infections in the absence of antibiotics.
CFTR (cystic fibrosis transmembrane conductance regulator)-knockout ferrets were treated with three antibiotics from birth to several years of age and lung disease was followed by quantitative computed tomography, BAL, and histopathology. Lung disease was compared with CFTR-knockout ferrets treated symptomatically with antibiotics.
Bronchiectasis was quantified from computed tomography images. BAL was evaluated for cellular differential and features of inflammatory cellular activation, bacteria, fungi, and quantitative proteomics. Semiquantitative histopathology was compared across experimental groups. We demonstrate that lifelong antibiotics can protect the CF ferret lung from infections for several years. Surprisingly, CF animals still developed hallmarks of structural bronchiectasis, neutrophil-mediated inflammation, and mucus accumulation, despite the lack of infection. Quantitative proteomics of BAL from CF and non-CF pairs demonstrated a mucoinflammatory signature in the CF lung dominated by Muc5B and neutrophil chemoattractants and products.
These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.
对囊性纤维化（CF）肺病发病机制的经典解释表明，感染引发疾病进展，导致过度的炎症反应、过多的黏液，最终导致支气管扩张。尽管早期症状的抗生素治疗可以控制肺部感染，但通常会导致细菌持续存在。控制 CF 肺部中持续细菌定植的过程以及非感染性成分对疾病发病机制的贡献仍知之甚少。
使用一种雪貂模型来评估连续抗生素治疗是否可以保护 CF 肺部免受疾病的影响，该模型在没有抗生素的情况下迅速发生致命的细菌性肺部感染。
从出生到几年大，CFTR（囊性纤维化跨膜电导调节因子）敲除雪貂接受三种抗生素治疗，并通过定量计算机断层扫描、BAL 和组织病理学来监测肺部疾病。将 CFTR 敲除雪貂的肺部疾病与接受抗生素对症治疗的 CFTR 敲除雪貂进行比较。
通过计算机断层扫描图像定量支气管扩张。BAL 用于评估细胞差异和炎症细胞激活、细菌、真菌和定量蛋白质组学的特征。比较了不同实验组之间的半定量组织病理学。我们证明，终身抗生素可以保护 CF 雪貂的肺部免受感染数年。令人惊讶的是，尽管没有感染，CF 动物仍然会发展为结构性支气管扩张、中性粒细胞介导的炎症和黏液积聚的特征。CF 和非 CF 配对的 BAL 定量蛋白质组学显示 CF 肺部的黏液炎症特征主要由 Muc5B 和中性粒细胞趋化因子及其产物主导。
这些发现表明，在没有临床明显的细菌和真菌感染的情况下，CF 肺部的黏液炎症过程是致病的。
