Residual cftr Expression Varies with Age in cftrtm1Hgu Cystic Fibrosis Mice: Impact on Morphology and Physiology

Abstract

Mouse models for cystic fibrosis (CF) mimic intestinal manifestations of the human disease, but the lung disease phenotypes are lacking in most strains. In this work, the issue was addressed whether aging of the respiratory tract leads to lung pathophysiology in the exon 10 insertional mutant cftr^tm1Hgu mouse. Weight gain, body weight and life-span of cftr^tm1Hgu mice were significantly reduced compared with control mice. cftr^tm1Hgu mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator (cftr) mRNA transcript in lungs, intestine and kidney. Wild-type cftr mRNA in renal and respiratory epithelia varied with age from levels similar to Ztm:MF1 controls at the age of 2 and 4 months to levels seen in patients with CFTR splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in cftr^tm1Hgu mice during their first year of life. The alveolar surfactant phospholipid pool was increased in cftr^tm1Hgu mice by 1.5- to 2-fold compared with Ztm:MF1 controls. Alveolar clearance of γ-labelled scandium oxide – the first report of lung clearance measurement in living mice – was reduced in cftr^tm1Hgu mice compared with littermate controls. Although no progressive lung pathology was seen in the cftr expression of cftr^tm1Hgu mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.