Editors' ChoiceCystic Fibrosis

Solving Cystic Fibrosis One Swine at a Time

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Science Translational Medicine  01 Dec 2010:
Vol. 2, Issue 60, pp. 60ec185
DOI: 10.1126/scitranslmed.3001964

For most people, the phrase “you take my breath away” has positive connotations. Not so for cystic fibrosis (CF) sufferers. Although treatments have improved, this genetic disease—caused by a mutation in the CF transmembrane conductance regulator (CFTR) gene—remains incurable and life-threatening, in part because researchers have lacked animal models that faithfully mimic the human disease. Recently, scientists discovered a mutation in the CFTR gene in pigs that spurred the development of a porcine CF model that closely matches the disease characteristics in humans. Now, using the CF pig models they developed, Meyerholz et al. demonstrate that early structural abnormalities in the CF airways could contribute to respiratory infections and the pathogenesis of the disease.

The CFTR gene encodes a chloride channel that, in CF patients, is defective in its ability to transport ions and water across cell membranes. This aberration gives rise to problems in the intestines, pancreas, liver, reproductive system, and, most ominously, the lungs—the site of complications that most often causes the morbidity and mortality associated with CF. Lung disease in CF patients is caused by infection and inflammation, and which comes first in CF pathogenesis has puzzled researchers. In the new work, the authors used computed tomography (CT) scans, pathology, and a morphometric approach to assess the differences between airways in newborn CFTR–/– pigs and their wild-type CFTR+/+ littermates. These studies revealed that the tracheas of CF pigs had smaller diameters and were less circular compared with those of the control animals. Furthermore, the tracheal smooth muscles showed tissue remodeling and enrichment of smooth muscle–specific genes, suggesting a trend toward increased smooth muscle volume only in the CF pigs. The authors also observed that the submucosal glands of the airway mucosa of neonatal CF pigs were hypoplastic—that is, they were underdeveloped and contained fewer cells than normal airways.

On the basis of these findings, Meyerholz et al. studied the tracheas of young CF patients (mean age, 1.7 years) using CT scans and analyzed previously published data on the airways of CF neonates. In partial agreement with the findings in CF pigs, the tracheas of the young CF patients were less circular than those of aged-matched control children but had similar lumen areas. On the other hand, the CF neonates, like their porcine counterparts, had both less-circular tracheas and smaller lumens compared with those of controls. These findings suggest that abnormalities in CF airway structure and function may begin early in fetal life. This knowledge may be useful in defining the cause of CF-associated airway abnormalities and how they effect the pathogenesis of CF, two prerequisites to the development of new preventive and therapeutic strategies.

D. K. Meyerholz et al., Loss of cystic fibrosis transmembrane conductance regulator function produces abnormalities in tracheal development in neonatal pigs and young children. Am. J. Respir. Crit. Care Med. 182, 1251–1261 (2010). [Abstract]

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