Cystic Fibrosis Pigs Develop Lung Disease and Exhibit Defective Bacterial Eradication at Birth

Abstract

NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptLung disease causes most of the morbidity and mortality in cystic fibrosis (CF). However, understanding its pathogenesis has been hindered by lack of an animal model with characteristic features of CF. To overcome this problem, we recently generated pigs with targeted CFTR genes. We now report that, within months of birth, CF pigs spontaneously develop hallmark features of CF lung disease including airway inflammation, remodeling, mucus accumulation, and infection. Their lungs contained multiple bacterial species, suggesting an equal opportunity host defense defect. In humans, the temporal and causal relationships between inflammation and infection have remained uncertain. To investigate these processes, we studied newborn pigs. Their lungs showed no inflammation, but were less often sterile than controls. Moreover, after intrapulmonary bacterial challenge, CF pigs failed to eradicate bacteria as effectively as wild-type pigs. These results suggest that impaired bacterial elimination is the pathogenic event that initiates a cascade of inflammation and pathology in CF lungs. Finding that CF pigs have a bacterial host defense defect within hours of birth provides an opportunity to further investigate pathogenesis and to test therapeutic and preventive strategies before secondary consequences develop.

Relationships among CFTR expression, HCO 3 − secretion, and host defense may inform gene- and cell-based cystic fibrosis therapies

“…An advantage is that we used a porcine model of CF that develops the characteristic features of CF lung disease (29,30). To avoid the effects of longterm infection and inflammation, including potential epigenetic changes in epithelial cells, we generated airway epithelia from newborn animals, which we previously showed exhibit airway host defense defects (30,31,33).…”

“…We previously developed an assay of ASL antimicrobial activity in which a small gold grid with attached bacteria is briefly touched to the ASL in vivo or in vitro and removed, and the percentage of nonviable bacteria is counted (33,34). We routinely use Staphylococcus aureus because it more commonly infects the airways of young children with CF and neonatal CF piglets than Pseudomonas aeruginosa (30,45). However, we have observed similar pH-dependent killing of P. aeruginosa (33,34).…”

“…At birth, their airways lack infection and inflammation, but, over the ensuing weeks and months, they develop the hallmark features of CF airway disease (30). By studying newborn CF piglets, we identified at least two airway host defense defects (2).…”

Pseudomonas aeruginosa triggers CFTR-mediated airway surface liquid secretion in swine trachea

“…Airway host defense is compromised in individuals with cystic fibrosis (CF), whose lungs are thus prone to chronic bacterial infections, frequently with Pseudomonas aeruginosa, and inflammation that may eventually cause lung tissue damage and respiratory failure (1,2). The events leading from cystic fibrosis transmembrane conductance regulator (CFTR) gene mutation to airway disease are incompletely understood, but accumulating evidence suggests that CF airway disease results from abnormal microbial clearance (3,4).…”

Bacterial host interactions in cystic fibrosis

“…More recently developed CF-pig and CF-ferret models demonstrated mucous gland secretions that resemble those of human CF [59,60]. The lungs of newborn CF-piglets showed evidence of airway obstruction and reduced eradication of instilled bacteria [61]. CF-ferrets showed a higher abundance of bacteria in two-day old animals, but this difference was not maintained in animals that died after one week [59].…”