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A murine model of cystic fibrosis
J N Snouwaert1, K K Brigman, A M Latour
1Department of Medicine, University of North Carolina at Chapel Hill 27599.
Abstract:
We have generated a mouse line in which the cystic fibrosis transmembrane conductance regulator (CFTR) gene has been mutated by gene targeting. Like human cystic fibrosis (CF) patients, mice lacking a functional CFTR gene, referred to as CFTR(-/-) mice, show increased numbers of goblet cells and obstruction of glands with inspissated eosinophilic secretions. The obstruction of glands often results in the destruction of gland-containing tissues in these animals. However, unlike the case in human CF patients, the most severe pathological changes in these mice were found, on preliminary analysis, to be confined to the intestinal tract and gallbladder. Although respiratory failure is the primary cause of death among humans with CF, we found only minor pathological alterations in the lungs and upper airways of our CFTR(-/-) animals. Possible explanations for the apparent lack of respiratory disease are the young age at which the animals were examined and the pathogen-free environment in which they were housed. In this manuscript, we examine the respiratory and other organ systems of CFTR(-/-) mice that have survived to adulthood. We also report on initial experiments in which CFTR(-/-) mice have been exposed to bacterial pathogens, and we present data on a single animal that displayed severe respiratory disease.
Insights
Mice lacking the cystic fibrosis transmembrane conductance regulator (CFTR) gene exhibit intestinal and gallbladder pathology, but minimal lung disease, unlike human cystic fibrosis patients. Further studies explored adult CFTR(-/-) mice and pathogen exposure.
Area of Science:
- Genetics and Molecular Biology
- Physiology
- Pathology
Background:
- Cystic fibrosis (CF) is a genetic disorder caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene.
- CFTR dysfunction leads to various organ system abnormalities, primarily respiratory failure in humans.
Purpose of the Study:
- To investigate the long-term effects of CFTR gene mutation in adult mice.
- To assess the respiratory and other organ systems in CFTR(-/-) mice.
- To evaluate the impact of bacterial pathogen exposure on CFTR(-/-) mice.
Main Methods:
- Generation of a mouse line with a targeted mutation in the CFTR gene (CFTR(-/-) mice).
- Histopathological examination of various organ systems in adult CFTR(-/-) mice.
- Exposure of CFTR(-/-) mice to bacterial pathogens.
Main Results:
- CFTR(-/-) mice displayed increased goblet cells and gland obstruction with secretions, primarily in the intestinal tract and gallbladder.
- Unlike human CF patients, CFTR(-/-) mice showed only minor lung and upper airway alterations in young animals.
- Adult CFTR(-/-) mice and pathogen-exposed animals exhibited varied responses, with one case of severe respiratory disease.
Conclusions:
- CFTR(-/-) mice serve as a model for certain aspects of CF pathology, particularly intestinal and gallbladder disease.
- The lack of severe respiratory disease in young, pathogen-free CFTR(-/-) mice may be due to age and environment.
- Further research is needed to fully understand the respiratory implications and potential for severe disease in CFTR(-/-) mice, especially upon pathogen challenge.