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A murine model of CF lung disease
  1. D McKeon
  1. CF Trust Research Fellow, Papworth Hospital, Cambridge, UK; mckeondoctors.org.uk

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CFTR null mice do not develop spontaneous pulmonary disease and the mechanistic link between altered ion transport and the pathogenesis of CF has remained unclear. In this paper, Mall et al have generated transgenic mice that overexpress the ENaC epithelial Na+ channel and discovered that these mice do develop airway obstruction, dehydrated mucus, goblet cell metaplasia, and neutrophilic airway inflammation which are the pathological features of early CF lung disease. This animal model demonstrates in vivo that one of the key functions of CFTR in the lower airway epithelium is to regulate the ENaC channel and thereby control sodium absorption and hydration of the periciliary liquid. Absence of CFTR leads to dehydration of the periciliary liquid and defective mucus transport.

In keeping with CF lung disease, these transgenic mice—in contrast to wild type—failed to clear bacteria from the lung following intratracheal instillation. Interestingly, even in the absence of bacterial infection, bronchoalveolar lavage fluid from the transgenic animals revealed increased neutrophil numbers and levels of proinflammatory cytokines. The authors’ explanation for this sterile neutrophilic infiltrate is that the abnormal mucociliary clearance prevents the removal of inhaled environmental particles which then trigger release of neutrophil attracting chemokines and the onset of inflammation.

This important work has provided insight into the pathogenesis of CF and provides a suitable murine model for potential therapeutic manipulation.

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