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First published online on January 4, 2007.
 Copyright © 2007 by The Physiological Society
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Received October 25, 2006
Revised November 24, 2006
Accepted after revision December 21, 2006

Mucus secretion by single tracheal submucosal glands from normal and CFTR knock-out mice

Juan P. Ianowski1, Jae Young Choi2, Jeffrey J. Wine2, and John W. Hanrahan1*

1 McGill University, Montreal, Quebec Canada H3G 1Y6
2 Stanford University, Jordan Hall, Stanford CA 94305-2130

* To whom correspondence should be addressed. E-mail: john.hanrahan{at}mcgill.ca.

Submucosal glands line the cartilaginous airways and produce most of the antimicrobial-rich mucus that keeps the airways sterile. The glands are defective in cystic fibrosis (CF), but how this impacts airway health remains uncertain. Although most CF mouse strains exhibit mild airway defects, those with the C57Bl/6 genetic background have increased airway pathology and susceptibility to Pseudomonas. Thus, they offer the possibility of studying if, and how, abnormal submucosal gland function contributes to CF airway disease. We used optical methods to study fluid secretion by individual glands in tracheas from normal, wild-type (WT) mice and from CF mice (CFTR knock-out mice Cftrm1UNC / Cftrm1UNC). Glands from WT mice qualitatively resembled those in humans by responding to carbachol and vasoactive intestinal peptide (VIP) although the relative rates of VIP- and forskolin-stimulated secretion were much lower in mice than in large mammals. The pharmacology of mouse gland secretion was also similar to that in humans; adding bumetanide or replacing HCO3- reduced the carbachol response by ~50%, and this inhibition increased to 80% when both maneuvers were performed simultaneously. Importantly, glands from CFTR knock-out mice responded to carbachol but did not secrete when exposed to VIP or forskolin, as has been shown previously for glands from CF patients. WT and CF tracheal glands both had robust secretory responses to electrical field stimulation that was blocked by tetrodotoxin. Interestingly, local irritation of the mucosa using chili pepper oil elicited secretion from WT glands but did not stimulate glands from CF mice. These results clarify the mechanisms of murine submucosal gland secretion and reveal a novel defect in local regulation of glands lacking CFTR which may also compromise airway defense in CF patients.


Key words: Airways • Cystic fibrosis • Mouse


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