Development of an airway mucus defect in the cystic fibrosis rat
Susan E. Birket, Joy M. Davis, Courtney M. Fernandez, Katherine L. Tuggle, Ashley M. Oden, Kengyeh K. Chu, Guillermo J. Tearney, Michelle V. Fanucchi, Eric J. Sorscher, Steven M. Rowe
Susan E. Birket, Joy M. Davis, Courtney M. Fernandez, Katherine L. Tuggle, Ashley M. Oden, Kengyeh K. Chu, Guillermo J. Tearney, Michelle V. Fanucchi, Eric J. Sorscher, Steven M. Rowe
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Research Article Cell biology Pulmonology

Development of an airway mucus defect in the cystic fibrosis rat

Abstract

The mechanisms underlying the development and natural progression of the airway mucus defect in cystic fibrosis (CF) remain largely unclear. New animal models of CF, coupled with imaging using micro-optical coherence tomography, can lead to insights regarding these questions. The Cftr–/– (KO) rat allows for longitudinal examination of the development and progression of airway mucus abnormalities. The KO rat exhibits decreased periciliary depth, hyperacidic pH, and increased mucus solid content percentage; however, the transport rates and viscoelastic properties of the mucus are unaffected until the KO rat ages. Airway submucosal gland hypertrophy develops in the KO rat by 6 months of age. Only then does it induce increased mucus viscosity, collapse of the periciliary layer, and delayed mucociliary transport; stimulation of gland secretion potentiates this evolution. These findings could be reversed by bicarbonate repletion but not pH correction without counterion donation. These studies demonstrate that abnormal surface epithelium in CF does not cause delayed mucus transport in the absence of functional gland secretions. Furthermore, abnormal bicarbonate transport represents a specific target for restoring mucus clearance, independent of effects on periciliary collapse. Thus, mature airway secretions are required to manifest the CF defect primed by airway dehydration and bicarbonate deficiency.

Authors

Susan E. Birket, Joy M. Davis, Courtney M. Fernandez, Katherine L. Tuggle, Ashley M. Oden, Kengyeh K. Chu, Guillermo J. Tearney, Michelle V. Fanucchi, Eric J. Sorscher, Steven M. Rowe

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Figure 5

Hyperacidic airway surface liquid and altered mucus are bicarbonate dependent.

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Hyperacidic airway surface liquid and altered mucus are bicarbonate depe...
pH of 3-month-old WT tracheae in normal conditions and in bicarbonate-free conditions compared with KO tracheae, was measured using a solid content pH probe (A). Solid content of the airway surface mucus in 3-month-old WT trachea under normal and bicarbonate-free conditions was also compared with KO trachea (B). Periciliary layer (PCL) depths of WT tracheae in normal conditions and in bicarbonate-free conditions, compared with KO trachea, obtained from μOCT imaging (C). μOCT imaging also yields mucociliary transport (MCT) rates at baseline (D) and after cholinergic stimulation (E). Particle-tracking microrheology (PTM) yields effective viscosity of WT tracheae in the presence and absence of bicarbonate, compared with KO (F). MCT rates compared with effective viscosity indicate a strong relationship between viscosity of the mucus and the rate at which it is transported across the trachea (G). However, MCT rates compared with the solid content percentage (1-month KO conditions marked by τ) (H) and the solid content percentage compared with viscosity (I) do not correlate in a statistically significant manner. Data are shown as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001. Data were analyzed by (A–C) 1-way ANOVA and (D–F) 2-way ANOVA. Data in A depict 3 regions of interest (ROIs) from 4 animals/group. Data in B are from 3 animals/group. Data in C are 4 ROIs from 6 animals/group. Data in D–I are from 6 animals/group.