Abstract
In the airways of those with cystic fibrosis (CF), the leading pathophysiological hypothesis is that an ion channel defect results in a relative decrease in airway surface liquid (ASL) volume, producing thick and sticky mucus that facilitates the establishment and progression of early fatal lung disease. This hypothesis predicts that any successful CF airway treatment for this fundamental channel defect should increase the ASL volume, but up until now there has been no method of measuring this volume that would be compatible with in vivo monitoring. In order to accurately monitor the volume of the ASL, we have developed a new x-ray phase contrast imaging method that utilizes a highly attenuating reference grid. In this study we used this imaging method to examine the effect of a current clinical CF treatment, aerosolized hypertonic saline, on ASL depth in ex vivo normal mouse tracheas, as the first step towards non-invasive in vivo ASL imaging. The ex vivo tracheas were treated with hypertonic saline, isotonic saline or no treatment using a nebuliser integrated within a small animal ventilator circuit. Those tracheas exposed to hypertonic saline showed a transient increase in the ASL depth, which continued for nine minutes post-treatment, before returning to baseline by twelve minutes. These findings are consistent with existing measurements on epithelial cell cultures, and therefore suggest promise for the future development of in vivo testing of treatments. Our grid-based imaging technique measures the ASL depth with micron resolution, and can directly observe the effect of treatments expected to increase ASL depth, prior to any changes in overall lung health. The ability to non-invasively observe micron changes in the airway surface, particularly if achieved in an in vivo setting, may have potential in pre-clinical research designed to bring new treatments for CF and other airway diseases to clinical trials.
Highlights
To maintain normal lung function, it is essential that the airways clear cellular debris or pathogens that deposit during respiration
The surface of the conducting airways are covered with microscopic hairs called cilia, located within the airway surface liquid (ASL), that provide the driving force for mucociliary clearance (MCC)
These pathogens contribute to the persistent infection that underlies the progressive lung disease and decreased respiratory function that is typical of cystic fibrosis (CF) [2]
Summary
To maintain normal lung function, it is essential that the airways clear cellular debris or pathogens that deposit during respiration. Bacteria and viruses are normally captured by the mucus layer and transported along the airway surface away from the lungs via cilia action until the material is directed into the oesophagus and swallowed. This defect results in a reduction in the ASL volume [3,4] and produces a relative dehydration of the airway surface such that MCC is compromised. The thickened and sticky mucus cannot be sufficiently cleared by MCC, resulting in retention of both mucus and inhaled pathogens. These pathogens contribute to the persistent infection that underlies the progressive lung disease and decreased respiratory function that is typical of CF [2]. CF impairs the function of a range of other organ systems, it is the chronic infectious airway and lung diseases that is the primary cause of a decreasing quality of life and an early death in most CF patients
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