Airway Remodeling in Ferrets with Cigarette Smoke Induced COPD using µCT Imaging

Am J Physiol Lung Cell Mol Physiol. 2020 May 6;319(1):L11-L20. doi: 10.1152/ajplung.00328.2019. Online ahead of print.

Abstract

Rationale: Structural changes to airway morphology such as increased bronchial wall thickness (BWT) and airway wall area are cardinal features of chronic obstructive pulmonary disease (COPD). Ferrets are a recently established animal model uniquely exhibiting similar clinical and pathological characteristics of COPD as humans, including chronic bronchitis.

Objectives: Develop a µCT method for evaluating structural changes to the airways in ferrets, and assess whether the effects of smoking induce changes consistent with chronic bronchitis in humans.

Methods: Ferrets were exposed to mainstream cigarette smoke or air control twice daily for 6 months. µCT was conducted in vivo at 6 months; a longitudinal cohort was imaged monthly. Manual measurements of BWT, luminal diameter (LD), and BWT:LD ratio were conducted, and confirmed by a semi-automated algorithm. The square root of bronchial wall area (WA) vs. luminal perimeter was determined on an individual ferret basis.

Measurements and main results: Smoke exposed ferrets reproducibly demonstrated 34% increased BWT (P<0.001); along with increased LD, and BWT:LD ratio vs. air controls. Regression indicated the effect of smoking on BWT persisted despite controlling for covariates. Semi-automated measurements replicated findings. WA for the theoretical median airway luminal perimeter of 4 mm (Pi4) was elevated 4.4% in smoke exposed ferrets (P=0.015). Increased BWT and Pi4 developed steadily over time.

Conclusions: µCT-based airway measurements in ferrets are feasible and reproducible. Smoke exposed ferrets develop increased BWT and Pi4, changes similar to humans with chronic bronchitis. µCT can be used as a significant translational platform to measure dynamic airway morphological changes.

Keywords: COPD; bronchial wall thickness; chronic bronchitis.