The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease

Zhou, Zhe; Duerr, Julia; Johannesson, Bjarki; Schubert, Susanne C.; Treis, Diana; Harm, Maria; Graeber, Simon Y.; Dalpke, Alexander; Schultz, Carsten; Mall, Marcus A.

doi:10.1016/S1569-1993(11)60021-0

« Previous Next »Journal of Cystic Fibrosis
Volume 10, Supplement 2 , Pages S172-S182, June 2011

The ENaC-overexpressing mouse as a model of cystic fibrosis lung disease

Zhe Zhou
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
Julia Duerr
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
Bjarki Johannesson
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany
Susanne C. Schubert
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
Diana Treis
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
Maria Harm
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
Simon Y. Graeber
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
Alexander Dalpke
- Department of Infectious Diseases, Medical Microbiology and Hygiene, University of Heidelberg, 69120 Heidelberg, Germany
Carsten Schultz
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
- European Molecular Biology Laboratory, Cell Biology and Biophysics Unit, 69117 Heidelberg, Germany
Marcus A. Mall
- Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, 69120 Heidelberg, Germany
- Molecular Medicine Partnership Unit, University of Heidelberg and European Molecular Biology Laboratory, 69120 Heidelberg, Germany
- Correspondence author: Marcus A. Mall, MD, Division of Pediatric Pulmonology & Allergy and Cystic Fibrosis Center, Department of Pediatrics III, University of Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany. Tel.: +49-6221-568840; fax.: +49-6221-568806

Abstract

Chronic lung disease remains the major cause of morbidity and mortality of cystic fibrosis (CF) patients. Cftr mutant mice developed severe intestinal obstruction, but did not exhibit the characteristic CF ion transport defects (i.e. deficient cAMP-dependent Cl⁻ secretion and increased Na⁺ absorption) in the lower airways, and failed to develop CF-like lung disease. These observations led to the generation of transgenic mice with airway-specific overexpression of the epithelial Na⁺ channel (ENaC) as an alternative approach to mimic CF ion transport pathophysiology in the lung. Studies of the phenotype of βENaC-transgenic mice demonstrated that increased airway Na⁺ absorption causes airway surface liquid (ASL) depletion, reduced mucus transport and a spontaneous CF-like lung disease with airway mucus obstruction and chronic airway inflammation. Here, we summarize approaches that can be applied for studies of the complex in vivo pathogenesis and preclinical evaluation of novel therapeutic strategies in this model of CF lung disease.

Keywords: Cystic fibrosis , Mouse model , ENaC , Airway surface liquid , Mucus obstruction , Airway inflammation