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Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets
Journal article   Open access   Peer reviewed

Infection Is Not Required for Mucoinflammatory Lung Disease in CFTR-Knockout Ferrets

Bradley H Rosen, T. Idil Apak Evans, Shashanna R Moll, Jaimie S Gray, Bo Liang, Xingshen Sun, Yulong Zhang, Chandler W Jensen-Cody, Anthony M Swatek, Weihong Zhou, …
American journal of respiratory and critical care medicine, Vol.197(10), pp.1308-1318
05/15/2018
DOI: 10.1164/rccm.201708-1616OC
PMCID: PMC5955060
PMID: 29327941
url
https://doi.org/10.1164/rccm.201708-1616OCView
Published (Version of record) Open Access

Abstract

Rationale: 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. Objectives: 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. Methods: 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. Measurements and Main Results: 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. Conclusions: These findings implicate mucoinflammatory processes in the CF lung as pathogenic in the absence of clinically apparent bacterial and fungal infections.
 Inflammation Cystic Fibrosis airway obstruction Original ferret mucus

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