Abstract
The mechanisms by which cigarette smoking impairs airway mucus clearance are not well understood. We recently established a ferret model of cigarette smoke-induced chronic obstructive pulmonary disease (COPD) exhibiting chronic bronchitis. We investigated the effects of cigarette smoke on mucociliary transport (MCT).
Adult ferrets were exposed to cigarette smoke for 6 months, with in vivo mucociliary clearance (MCC) measured by Tc-labeled DTPA (Tc-DTPA) retention. Excised tracheae were imaged with micro-optical coherence tomography. Mucus changes in primary human airway epithelial cells and ex vivo ferret airways were assessed by histology and particle tracking microrheology. Linear mixed models for repeated measures identified key determinants of MCT.
Compared to air controls, cigarette smoke-exposed ferrets exhibited mucus hypersecretion, delayed MCC (−89.0%, p<0.01), and impaired tracheal MCT (−29.4%, p<0.05). Cholinergic stimulus augmented airway surface liquid (ASL) depth (5.8±0.3 to 7.3±0.6 µm, p<0.0001) and restored MCT (6.8±0.8 to 12.9±1.2 mm·min−1, p<0.0001). Mixed model analysis controlling for covariates indicated smoking exposure, mucus hydration (ASL) and CBF were important predictors of MCT. Ferret mucus was hyperviscous following smoke exposure in vivo or in vitro and contributed to diminished MCT. Primary cells from smokers with and without COPD recapitulated these findings, which persisted despite the absence of continued smoke exposure.
Cigarette smoke impairs MCT by inducing airway dehydration and increased mucus viscosity, and can be partially abrogated by cholinergic secretion of fluid secretion. These data elucidate the detrimental effects of cigarette smoke exposure on mucus clearance and suggest additional avenues for therapeutic intervention.
Footnotes
This manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.
Conflict of interest: Dr. Lin has nothing to disclose.
Conflict of interest: Dr. Kaza has nothing to disclose.
Conflict of interest: Dr. Birket has nothing to disclose.
Conflict of interest: Dr. Kim has nothing to disclose.
Conflict of interest: Dr. Edwards has nothing to disclose.
Conflict of interest: Ms. LaFontaine has nothing to disclose.
Conflict of interest: Dr. Liu reports In addition, Dr. Liu has a patent Method for functional investigation of respiratory airways and other ciliated tissues using µOCT pending.
Conflict of interest: Ms. Mazur has nothing to disclose.
Conflict of interest: Mr. Byzek has nothing to disclose.
Conflict of interest: Dr. Hanes reports other from GrayBug Vision, Inc., other from Kala Pharmaceuticals, Inc., outside the submitted work.
Conflict of interest: Dr. Tearney reports In addition, Dr. Tearney has a patent 14/240,938 pending, and a patent 12826303.5 pending.
Conflict of interest: Dr. Raju has nothing to disclose.
Conflict of interest: Dr. Rowe reports grants from Bayer, grants from Forest Research Institute, grants from AstraZeneca, grants from N30/Nivalis, grants from Novartis, grants from Galapagos/AbbVie, grants from Proteostasis, grants from Eloxx, grants and personal fees from Celtaxsys, grants from PTC Therapeutics , grants, personal fees and non-financial support from Vertex Pharmaceuticals Incorporated, personal fees from Bayer, personal fees from Novartis, outside the submitted work; In addition, Dr. Rowe has a patent Use of OCT as a diagnostic modality for diseases of mucus clearance.
- Received February 28, 2019.
- Accepted October 9, 2019.
- Copyright ©ERS 2019
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