Radiographic assessment of lung anatomy, physiology, and disease in a porcine model of cystic fibrosis and people with cystic fibrosis

Despite affecting many organ systems, the leading cause of morbidity and mortality in the cystic fibrosis (CF) population is lung disease. For the current studies we investigated elements of CF lung disease in a porcine model of CF and in people with CF. Our primary analysis tool was chest computed tomography (CT).

To investigate early CF lung disease we examined three week old CF and non-CF pigs. We found three week old CF pigs to have large, irregular tracheal smooth muscle bundles, airways of reduced size, airways of irregular shape, and airways of abnormal distensibility.

Three week old CF pig lung parenchyma was more heterogenous in density than three week non-CF pigs, especially in the right cephalad lung. The degree of lung tissue heterogeneity in CF pigs correlated with the degree of lung infection. Three week old CF pigs also had significantly more air trapping upon exhalation, evidence of airflow obstruction, than non-CF pigs. The degree of air trapping correlated with the degree of mucus accumulation in the airways. These data show that CF pigs spontaneously develop hallmark features of CF lung disease within weeks of birth, and that abnormal airway growth and development in CF may contribute to lung disease. This study helped set the foundation for future comparative studies involving CF therapeutics, for example, antibiotics and mucolytics.

In adults with CF we performed a before drug, after drug study. The drug was ivacaftor, and it restores the basic underlying defect in a subset of people with CF: impaired function of a particular anion channel. We hypothesized that abnormal airway smooth muscle behavior in people with CF, known as “CF asthma,” is, in part, a primary pathogenic mechanism of CF lung disease. We tested our hypothesis by assaying smooth muscle tone before and after administration of ivacaftor. We limited the time duration to two days. We reasoned two days was long enough for ivacaftor to become effective, but not long enough to reverse long standing lung infection and inflammation which could affect smooth muscle function independently. The implication being, that observed changes would be directly due to restoration of the CF defect. We found evidence suggesting relaxation of airway and vascular smooth muscle tone. And, the change in airway smooth muscle tone correlated with the change in vascular smooth muscle tone. These data suggest that impaired smooth muscle function is a primary element of CF lung disease.

Many of the people in our two day ivacaftor study returned for follow up after one year of ivacaftor therapy. We hypothesized that radiographic features of lung disease would improve following one year of ivacaftor therapy. We observed no change in lung volume upon inspiration, but a reduction in expiratory lung volume, approximately half of which occurred within two days. Our airway measurements were confounded by errors in scan reconstruction, however, other published studies report airway wall thinning over long term ivacaftor administration. Taken together, these studies of pigs with CF and people with CF, help us understand this disease.