The relationship of chronic mucin secretion to airway disease in normal and CFTR-deficient mice

In the cystic fibrosis (CF) patient, lung function decreases throughout lif e as a result of continuous cycles of infection, particularly with Pseudomo nas aeruginosa and Staphylococcus aureus. The mechanism underlying the path ophysiology of the disease in humans has not been established. However, it has been suggested that abnormal, tenacious mucus, resulting perhaps from i mproper hydration from loss of Cl- secretion via the cystic fibrosis transm embrane conductance regulator (CFTR) protein, impairs clearance of bacteria from the CF airway and provides an environment favorable to bacterial grow th. If this hypothesis is correct, it could explain the absence of respirat ory disease in CFTR-deficient mice, since mice have only a single submucosa l gland and display few goblet cells in their lower airways, even when expo sed to bacteria. To test this hypothesis further, we induced allergic airwa y disease in CFTR-deficient mice. We found that induction of allergic airwa y disease in mice, unlike bacterial infection, results in an inflammatory r esponse characterized by goblet cell hyperplasia, increased mucin gene expr ession, and increased production of mucus. However, we also found that dise ase progression and resolution is identical in Cftr(-/-) mice and control a nimals. Furthermore, we show that the presence of mucus in the Cftr(-/-) ai rway does not lead to chronic airway disease, even upon direct inoculation with S. aureus and P. aeruginosa. Therefore, factors in addition to the abs ence of high levels of mucus secretion protect the mouse from the airway di sease seen in human CF patients.