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J Physiol Volume 586, Number 13, 3231-3243, July 1, 2008 DOI: 10.1113/jphysiol.2008.150763
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RESPIRATORY

Congenital tracheal malformation in cystic fibrosis transmembrane conductance regulator-deficient mice

 Elise Bonvin1,2, Philippe Le Rouzic1,2, Jean-François Bernaudin1,3, Charles-Henry Cottart4, Clarisse Vandebrouck5,6, Antoine Crié1, Teresinha Leal7, Annick Clement1,2,8 and Monique Bonora1,2

1 UPMC Université Paris 06, F-75005 Paris, France
2 Inserm, U 719, F-75012 Paris, France
3 EA 3499, F-75020 Paris, France
4 EA 3617, Université René Descartes, Faculté de Pharmacie, F-75005 Paris, France
5 Université de Poitiers, F-86022 Poitiers, France
6 CNRS, UMR 6187, F-86022 Poitiers, France
7 Université Catholique de Louvain, Bruxelles, Belgique
8 AP-HP, Hôpital Trousseau, F-75012, Paris, France

In cystic fibrosis (CF) patients, the major alteration in pulmonary function is due to peripheral airway obstruction. In the present study, we investigated the possibility that alterations in the extrathoracic airways, particularly in the trachea that expresses high levels of CFTR (CF transmembrane conductance regulator), may contribute to respiratory dysfunction. We performed morphological analyses of the trachea and airway functional studies in adult Cftr knockout (Cftr–/–) and F508del-CFTR mice and their controls. Macroscopic and histological examination of the trachea showed the presence of one to seven disrupted or incomplete cartilage rings in Cftr–/– mice (23/25) while only a few Cftr+/+ mice (6/25) had one abnormal ring. Tracheal defects were mainly localized in the proximal trachea. In 14 Cftr–/– mice, frontal disruption of the first three to six rings below the cricoid cartilage were associated with upper tracheal constriction. Similar tracheal abnormalities were detected in adult F508del-CFTR and in newborn Cftr–/– and F508del-CFTR mice. Tracheal and ventilatory function analyses showed in Cftr–/– mice a decreased contractile response of the proximal trachea and a reduced breathing rate due to an increase in the inspiratory and expiratory times. In F508del-CFTR mice, the expiratory time was longer than in controls. Therefore, these structural and functional abnormalities detected in adult and newborn CF mouse models may represent congenital malformations related to CFTR dysfunction. These results raise important questions concerning the mechanisms governing tracheal development within the context of CFTR protein dysfunction and the implication of such abnormalities in the pathogenesis of airway disease in CF.

(Received 8 January 2008; accepted after revision 28 April 2008; first published online 1 May 2008)
Corresponding author M. Bonora: Inserm, UMRS 893, Eq 12, Hôpital Saint-Antoine, Bâtiment Kourilsky, 184, rue du Faubourg Saint-Antoine, Paris, 75012 France. Email: bonora{at}st-antoine.inserm.fr






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