Ivacaftor partially corrects airway inflammation in a humanized G551D rat.
Am J Physiol Lung Cell Mol Physiol
; 320(6): L1093-L1100, 2021 06 01.
Article
en En
| MEDLINE
| ID: mdl-33825507
Animal models have been highly informative for understanding the pathogenesis and progression of cystic fibrosis (CF) lung disease. In particular, the CF rat models recently developed have addressed mechanistic causes of the airway mucus defect characteristic of CF, and how these may change when cystic fibrosis transmembrane conductance regulator (CFTR) activity is restored using new modulator therapies. We hypothesized that inflammatory changes to the airway would develop spontaneously and progressively, and that these changes would be resolved with modulator therapy. To test this, we used a humanized-CFTR rat expressing the G551D variant that responds to the CFTR modulator ivacaftor. Markers typically found in the CF lung were assessed, including neutrophil influx, small airway histopathology, and inflammatory cytokine concentration. Young hG551D rats did not express inflammatory cytokines at baseline but did upregulate these in response to inflammatory trigger. As the hG551D rats aged, histopathology worsened, accompanied by neutrophil influx into the airway and increasing concentrations of TNF-α, IL-1α, and IL-6 in the airways. Ivacaftor administration reduced concentrations of these cytokines when administered to the rats at baseline but was less effective in the rats that had also received inflammatory stimulus. Therefore, we conclude that administration of ivacaftor resulted in an incomplete resolution of inflammation when rats received an external trigger, suggesting that CFTR activation may not be enough to resolve inflammation in the lungs of patients with CF.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Transporte Iónico
/
Quinolonas
/
Fibrosis Quística
/
Aminofenoles
/
Inflamación
Tipo de estudio:
Prognostic_studies
Límite:
Animals
Idioma:
En
Revista:
Am J Physiol Lung Cell Mol Physiol
Asunto de la revista:
BIOLOGIA MOLECULAR
/
FISIOLOGIA
Año:
2021
Tipo del documento:
Article
Pais de publicación:
Estados Unidos