Lessons learned from the cystic fibrosis pig

Abstract

Deficient function in the anion channel cystic fibrosis (CF) transmembrane conductance regulator is the fundamental cause for CF. This is a monogenic condition that causes lesions in several organs including the respiratory tract, pancreas, liver, intestines, and reproductive tract. Lung disease is most notable, given it is the leading cause of morbidity and mortality in people with CF. Shortly after the identification of CF transmembrane conductance regulator, CF mouse models were developed that did not show spontaneous lung disease as seen in humans, and this spurred development of additional CF animal models. Pig models were considered a leading choice for several reasons including their similarity to humans in respiratory anatomy, physiology, and in size for translational imaging. The first CF pig models were reported in 2008 and have been extremely valuable to help clarify persistent questions in the field and advance understanding of disease pathogenesis. Because CF pigs are susceptible to lung disease like humans, they have direct utility in translational research. In addition, CF pig models are useful to compare and contrast with current CF mouse models, human clinical studies, and even newer CF animal models being characterized. This "triangulation" strategy could help identify genetic differences that underlie phenotypic variations, so as to focus and accelerate translational research.

Keywords: Animal model; CFTR; Cystic fibrosis; Lung disease; Pig model.

Figure 1

Human CF lung from an archival autopsy tissue block. Note the CF airway lumen is obstructed (arrows) by neutrophilic cellular inflammation and some mucus. Bar = 800 μm.

Figure 2

Proposed relationship(s) between deficient CFTR function and CF lung disease. Deficient CFTR function causes proximate effects that in turn create a local environment for development of clinical effects eventually manifesting as CF lung disease. While these relationships are still being clarified, the CF pig model has been instrumental to begin understanding these complex relationships.