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Published on: April 21, 2022
Muc5b Contributes to Mucus Abnormality in Rat Models of Cystic Fibrosis
Johnathan D Keith1, Alexander G Henderson1, Courtney M Fernandez-Petty1
1Department of Medicine, Gregory Fleming James Cystic Fibrosis Research Center, University of Alabama at Birmingham, Birmingham, AL, United States.
Abstract:
Cystic fibrosis (CF) airway disease is characterized by excessive and accumulative mucus in the airways. Mucociliary clearance becomes defective as mucus secretions become hyperconcentrated and viscosity increases. The CFTR-knockout (KO) rat has been previously shown to progressively develop delayed mucociliary transport, secondary to increased viscoelasticity of airway secretions. The humanized-G551D CFTR rat model has demonstrated that abnormal mucociliary clearance and hyperviscosity is reversed by ivacaftor treatment. In this study, we sought to identify the components of mucus that changes as the rat ages to contribute to these abnormalities. We found that Muc5b concentrations, and to a lesser extent Muc5ac, in the airway were increased in the KO rat compared to WT, and that Muc5b concentration was directly related to the viscosity of the mucus. Additionally, we found that methacholine administration to the airway exacerbates these characteristics of disease in the KO, but not WT rat trachea. Lastly we determined that at 6 months of age, CF rats had mucus that was adherent to the airway epithelium, a process that is reversed by ivacaftor therapy in the hG551D rat. Overall, these data indicate that accumulation of Muc5b initiates the muco-obstructive process in the CF lung prior to infection.
Insights
In cystic fibrosis (CF) airway disease, increased Muc5b mucus accumulation drives airway obstruction. Ivacaftor treatment reversed mucus abnormalities and adherence in CF models.
Area of Science:
- Pulmonary Medicine
- Mucus Biochemistry
- Genetics and Disease Models
Background:
- Cystic fibrosis (CF) is characterized by defective mucociliary clearance due to hyperconcentrated, viscous airway mucus.
- CFTR-knockout (KO) rats exhibit delayed mucociliary transport and increased mucus viscoelasticity.
- Ivacaftor treatment in humanized-G551D CFTR rats reverses abnormal mucociliary clearance and mucus hyperviscosity.
Purpose of the Study:
- To identify age-related changes in mucus composition contributing to CF airway abnormalities.
- To investigate the role of specific mucins in CF mucus dysfunction.
- To assess the impact of methacholine on CF airway mucus properties.
Main Methods:
- Quantification of Muc5b and Muc5ac concentrations in CFTR-KO and wild-type (WT) rat airways.
- Measurement of mucus viscosity and correlation with mucin concentrations.
- Assessment of methacholine-induced changes in tracheal mucus properties in KO and WT rats.
- Evaluation of mucus adherence to airway epithelium in CF models and response to ivacaftor.
Main Results:
- Muc5b and, to a lesser extent, Muc5ac concentrations were elevated in KO rats compared to WT.
- Muc5b concentration directly correlated with mucus viscosity.
- Methacholine exacerbated airway mucus characteristics in KO rats but not WT rats.
- CF rats at 6 months showed mucus adherence to the airway epithelium, reversed by ivacaftor in hG551D rats.
Conclusions:
- Accumulation of Muc5b is a key initiator of muco-obstructive disease in CF lungs before infection.
- Mucus adherence to the airway epithelium is a feature of CF disease.
- Ivacaftor therapy can reverse mucus adherence and viscosity in CF models.
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