Residual <i>cftr</i> Expression Varies with Age in <i>cftr<sup>tm1Hgu</sup></i> 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 <i>cftr<sup>tm1Hgu</sup></i> mouse. Weight gain, body weight and life-span of <i>cftr<sup>tm1Hgu</sup></i> mice were significantly reduced compared with control mice. <i>cftr<sup>tm1Hgu</sup></i> mice expressed 20, 21 or 37% (median) of wild-type cystic fibrosis conductance transmembrane regulator <i>(cftr)</i> mRNA transcript in lungs, intestine and kidney. Wild-type <i>cftr</i> 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 <i>CFTR</i> splice mutations beyond the age of 6 months. The morphology of the bronchi and more distal airways was apparently normal in <i>cftr<sup>tm1Hgu</sup></i> mice during their first year of life. The alveolar surfactant phospholipid pool was increased in <i>cftr<sup>tm1Hgu</sup></i> 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 <i>cftr<sup>tm1Hgu</sup></i> mice compared with littermate controls. Although no progressive lung pathology was seen in the <i>cftr</i> expression of <i>cftr<sup>tm1Hgu</sup></i> mice, surfactant phospholipid homeostasis, and alveolar and mucociliary clearance were abnormal. Therefore, the described model is useful for studying the initial CF lung pathophysiology.