Airway disease phenotypes in animal models of cystic fibrosis

Abstract

In humans, cystic fibrosis (CF) lung disease is characterised by chronic infection, inflammation, airway remodelling, and mucus obstruction. A lack of pulmonary manifestations in CF mouse models has hindered investigations of airway disease pathogenesis, as well as the development and testing of potential therapeutics. However, recently generated CF animal models including rat, ferret and pig models demonstrate a range of well characterised lung disease phenotypes with varying degrees of severity. This review discusses the airway phenotypes of currently available CF animal models and presents potential applications of each model in airway-related CF research.

The epithelial sodium channel (ENaC) as a therapeutic target for cystic fibrosis

“…CF knockout animals, including mice, rats, rabbits, ferrets, and pigs, have been produced which recapitulate human CF disease with varying degrees of faithfulness [62]. Further, other models of CF lung disease such as the βENaC-transgenic mouse have also been useful for preclinical studies of CF [23,26]. Although models such as these produce CF-like lung disease as a consequence of significant airway dehydration, they do not fully recapitulate all of the potential pathologies involved in CF lung disease such as acidification of the airways and production of hyperviscous mucus.…”

“…In support of continued development of ENaC therapeutics in CF, empirical evidence demonstrates that aberrant ENaC activity contributes to either hyper- or hypo-hydrated ASL, with corresponding effects on mucociliary clearance (MCC) rate [23–26]. Indeed, mutations in the SCNN1A and B genes, which encode the α- and β-subunits of the ENaC protein, respectively, have been associated with CF-like lung disease in the absence of disease-causing CFTR mutations [6].…”

“…For example, a patient possessing a gain-of-function mutation [27] in the SCNN1B gene (V348M) was identified as having CF-like symptoms in the absence of CFTR mutations [28]. This phenomenon has been recapitulated in a murine model overexpressing the β-subunit of the ENaC protein [23,26]. Conversely, mutations causing hypoactivity of the ENaC channel have been shown to cause pseudohypoaldosteronism [6,24,29], which expands the ASL depth and accelerates the MC [29].…”

Mucoviscidosis: fisiopatología, genética, aspectos clínicos y terapéuticos

“…Las bases moleculares de la regulación negativa de la proteína CFTR sobre el ENaC todavía no se conocen bien [7] . [7][8][9][10] La disfunción de la proteína CFTR conduce a una falta de secreción de Cl -(que involucra a la proteína CFTR y a otros canales Clque ésta corregula) y a la hiperabsorción de Na + (debida a la supresión de la inhibición de la actividad de los canales ENaC) [7] . En condiciones basales, la hiperabsorción de Na + conduce a la absorción pasiva de Cly, por tanto, de agua.…”

“…El primum movens de la deshidratación acuosa sería un defecto en la secreción aniónica en respuesta al AMPc. Esto es particularmente sugerido por el modelo porcino, el cual mostraría sólo un defecto aislado de la secreción de Clsin aumento de la absorción de Na + [9] . Por lo tanto, en la actualidad, el debate no puede decidirse entre la hiperabsorción y la hiposecreción.…”