Lessons learned from the cystic fibrosis pig

Abstract

Deficient function in the anion channel cystic fibrosis transmembrane conductance regulator (CFTR) is the fundamental cause for cystic fibrosis (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 CFTR, 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.

Cystic fibrosis lung environment and Pseudomonas aeruginosa infection

“…Mendoza et al [38] also described mutations in the coupling helix of ICL4 that cause ER retention (L1065P, R1066C, and G1069R), supporting the idea that this region does play a role in mediating significant interactions during folding. For details of CFTR protein function, readers are referred to articles by Borowitz, Eborn, and Meyerholz [20, 40, 41]. …”

Inflammation and host-pathogen interaction: Cause and consequence in cystic fibrosis lung disease

“…The lungs of CF ferrets do not display lung infections when treated with antibiotics from birth, but do show neutrophil dominated inflammation and bronchiectasis [9]. However, although CF pigs lacked detectable pulmonary inflammation at birth, large airway remodelling was evident and the lungs from CF pigs were less sterile and had higher bacterial counts suggesting that infection may precede inflammation in this model [10]. While most of the studies in animal models are focused to the early phases of the disease, long-term chronic infection remains less investigated.…”

“…CF is the first human genetic disease to benefit from the directed engineering of several different species of animal models defective for the Cftr gene (mice, pigs, ferrets, rats, rabbit and, more recently, sheep), and one additional modelthe Scnn1b-Tg mice -with airway-specific overexpression of the βENaC subunit as an alternative approach to mimic CF ion transport pathophysiology in the lung [10,35,37,38]. Each of these models and their comparisons can assist our understanding of the mechanisms behind the exacerbated inflammation and infection in CF lungs.…”

Insights into host–pathogen interactions from state‐of‐the‐art animal models of respiratory Pseudomonas aeruginosa infections

“… compares different clinical manifestations of CFTR mutations between mouse, pig, and human, and despite the problems, highlights the great potential of the available animal model systems. In addition, there are additional comprehensive reviews on CF animal models . However, an ideal animal model that fully mimics the different facets of CF as well as chronic biofilm‐associated lung infections is currently not available.…”