Patients with cystic fibrosis (CF) suffer from the consequences of deficient CFTR (CF transmembrane conductance regulator gene) activity (1). CFTR controls epithelial chloride and sodium transport, with deficient function altering tissue milieu hydration, cellular membrane potential, and cellular functions, resulting in a multiorgan disease (2). The consequences of this pathophysiology results in increased mucous viscosity, mucus plugging, inflammation, and infection that ultimately destroys the lungs (3, 4). Unfortunately, to date, there are no therapeutic panaceas for CF. Even with small molecule CFTR correctors and potentiators, the established pulmonary damage still requires supplemental avenues of therapeutic intervention (5). The pursuit of new treatments requires the right model of choice for determining potency, efficacy, and adverse effects (6). The modeling system requires that the tissue pathophysiology be consistent both with the target of treatment and with the complexity of enhanced mucus viscosity/plugging, inflammation, and infection (7). The primary challenge to developing new therapeutics for CF is the lack of a readily accessible, cost-effective model system that allows for the simultaneous evaluation of mucociliary clearance abnormalities, infection susceptibilities, and inflammation (8). The Cftr-deficient mouse model does not have mucus/mucociliary clearance manifestations but does provide important insight into immune mechanisms associated with CF-deficient management of infection and inflammation. The bENaC (b epithelial sodium channel) mouse model has altered sodium ion transport, resulting in enhanced mucous viscosity and sustained inflammation, but does not have many of the other anomalies associated with deficient Cftr (9). In the case of the bENaC mouse model, additional therapeutic testing translated to a Cftr-deficient scenario assures an evaluation of other potential complications because of deficient Cftr. The cost of breeding mice, the short reproductive cycle, and the production of large litters streamlines numbers for efficiently powered studies with a lower cost in husbandry than the larger animal counterparts (10, 11). However, mice are not humans, and they do not recapitulate all aspects of CF pathophysiology.

The CF research community has continued to create in vivo models that more effectively reproduce many of the pathophysiological consequences of deficient CFTR function. The CF pig and ferret have been highly interrogated and are effective at recapitulating many of the components of CF (9, 11–13). Both the CF pig and ferret have similar pulmonary anatomy to humans, and a pathophysiology that more closely mimics that of CF in humans, including inefficient mucociliary clearance, excessive inflammation, and susceptibility to infection (13, 14). The CF rabbit and rat are newer models, less well established for translatability to the human disease, but the developers are steadily making progress (11, 15, 16).