Mucosal bromodomain-containing protein 4 mediates aeroallergen-induced inflammation and remodeling.
J Allergy Clin Immunol
; 143(4): 1380-1394.e9, 2019 04.
Article
en En
| MEDLINE
| ID: mdl-30321559
ABSTRACT
BACKGROUND:
Frequent exacerbations of allergic asthma lead to airway remodeling and a decrease in pulmonary function, producing morbidity. Cat dander is an aeroallergen associated with asthma risk.OBJECTIVE:
We sought to elucidate the mechanism of cat dander-induced inflammation-remodeling.METHODS:
We identified remodeling in mucosal samples from allergic asthma by using quantitative RT-PCR. We developed a model of aeroallergen-induced experimental asthma using repetitive cat dander extract exposure. We measured airway inflammation using immunofluorescence, leukocyte recruitment, and quantitative RT-PCR. Airway remodeling was measured by using histology, collagen content, myofibroblast numbers, and selected reaction monitoring. Inducible nuclear factor κB (NF-κB)-BRD4 interaction was measured by using a proximity ligation assay in situ.RESULTS:
Enhanced mesenchymal signatures are observed in bronchial biopsy specimens from patients with allergic asthma. Cat dander induces innate inflammation through NF-κB signaling, followed by production of a profibrogenic mesenchymal transition in primary human small airway epithelial cells. The IκB kinase-NF-κB signaling pathway is required for mucosal inflammation-coupled airway remodeling and myofibroblast expansion in the mouse model of aeroallergen exposure. Cat dander induces NF-κB/RelA to complex with and activate BRD4, resulting in modifying the chromatin environment of inflammatory and fibrogenic genes through its atypical histone acetyltransferase activity. A novel small-molecule BRD4 inhibitor (ZL0454) disrupts BRD4 binding to the NF-κB-RNA polymerase II complex and inhibits its histone acetyltransferase activity. ZL0454 prevents epithelial mesenchymal transition, myofibroblast expansion, IgE sensitization, and fibrosis in airways of naive mice exposed to cat dander.CONCLUSIONS:
NF-κB-inducible BRD4 activity mediates cat dander-induced inflammation and remodeling. Therapeutic modulation of the NF-κB-BRD4 pathway affects allergen-induced inflammation, epithelial cell-state changes, extracellular matrix production, and expansion of the subepithelial myofibroblast population.Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Asma
/
Factores de Transcripción
/
Proteínas de Ciclo Celular
/
Mucosa Respiratoria
/
Remodelación de las Vías Aéreas (Respiratorias)
/
Inflamación
Tipo de estudio:
Observational_studies
/
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Año:
2019
Tipo del documento:
Article