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The relationship of chronic mucin secretion to airway disease in normal and CFTR-deficient mice
V L Cressman1, E M Hicks, W K Funkhouser
1Curriculum in Genetics and Molecular Biology, Department of Medicine, and Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, North Carolina, USA.
Abstract:
In the cystic fibrosis (CF) patient, lung function decreases throughout life as a result of continuous cycles of infection, particularly with Pseudomonas aeruginosa and Staphylococcus aureus. The mechanism underlying the pathophysiology of the disease in humans has not been established. However, it has been suggested that abnormal, tenacious mucus, resulting perhaps from improper hydration from loss of Cl- secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) protein, impairs clearance of bacteria from the CF airway and provides an environment favorable to bacterial growth. If this hypothesis is correct, it could explain the absence of respiratory disease in CFTR-deficient mice, since mice have only a single submucosal gland and display few goblet cells in their lower airways, even when exposed to bacteria. To test this hypothesis further, we induced allergic airway disease in CFTR-deficient mice. We found that induction of allergic airway disease in mice, unlike bacterial infection, results in an inflammatory response characterized by goblet cell hyperplasia, increased mucin gene expression, and increased production of mucus. However, we also found that disease progression and resolution is identical in Cftr-/- mice and control animals. Furthermore, we show that the presence of mucus in the Cftr-/- airway does not lead to chronic airway disease, even upon direct inoculation with S. aureus and P. aeruginosa. Therefore, factors in addition to the absence of high levels of mucus secretion protect the mouse from the airway disease seen in human CF patients.
Insights
Cystic fibrosis (CF) patients experience declining lung function due to mucus buildup and infections. This study found that even with increased mucus, CFTR-deficient mice did not develop chronic lung disease, suggesting other protective factors are at play.
Area of Science:
- Pulmonary Medicine
- Genetics
- Microbiology
Background:
- Cystic fibrosis (CF) is characterized by progressive lung function decline, linked to mucus accumulation and bacterial infections like Pseudomonas aeruginosa and Staphylococcus aureus.
- The exact pathophysiology in humans remains unclear, but impaired chloride secretion via the cystic fibrosis transmembrane conductance regulator (CFTR) protein may cause abnormal mucus, hindering bacterial clearance.
- CFTR-deficient mice lack significant mucus hypersecretion, explaining their resistance to respiratory disease despite bacterial exposure.
Purpose of the Study:
- To investigate the role of mucus in CF lung disease by inducing allergic airway disease in CFTR-deficient mice.
- To determine if increased mucus production in CFTR-deficient mice leads to chronic airway disease.
- To identify potential factors protecting mice from CF-like airway pathology.
Main Methods:
- Induction of allergic airway disease in Cftr-/- mice and control littermates.
- Assessment of inflammatory responses, including goblet cell hyperplasia, mucin gene expression, and mucus production.
- Direct inoculation of Cftr-/- mice with Pseudomonas aeruginosa and Staphylococcus aureus.
Main Results:
- Allergic airway disease induced goblet cell hyperplasia, increased mucin expression, and mucus production in Cftr-/- mice.
- Disease progression and resolution were similar in Cftr-/- mice and control animals.
- The presence of mucus in Cftr-/- airways did not result in chronic airway disease, even after bacterial inoculation.
Conclusions:
- Increased mucus production alone does not cause chronic airway disease in the absence of functional CFTR.
- Mice possess protective mechanisms against CF-like airway disease beyond the absence of high mucus levels.
- Further research is needed to elucidate the factors that protect mice and differ from human CF pathophysiology.