Inhibition of MRTF activation as a clinically achievable anti-fibrotic mechanism for pirfenidone.
Eur Respir J
; 61(4)2023 04.
Article
em En
| MEDLINE
| ID: mdl-36585256
ABSTRACT
BACKGROUND:
Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease characterised by aberrant fibroblast/myofibroblast accumulation and excessive collagen matrix deposition in the alveolar areas of lungs. As the first approved IPF medication, pirfenidone (PFD) significantly decelerates lung function decline while its underlying anti-fibrotic mechanism remains elusive.METHODS:
We performed transcriptomic and immunofluorescence analyses of primary human IPF tissues.RESULTS:
We showed that myocardin-related transcription factor (MRTF) signalling is activated in myofibroblasts accumulated in IPF lungs. Furthermore, we showed that PFD inhibits MRTF activation in primary human lung fibroblasts at clinically achievable concentrations (half-maximal inhibitory concentration 50-150â µM, maximal inhibition >90%, maximal concentration of PFD in patients <100â µM). Mechanistically, PFD appears to exert its inhibitory effects by promoting the interaction between MRTF and actin indirectly. Finally, PFD-treated IPF lungs exhibit significantly less MRTF activation in fibroblast foci areas than naïve IPF lungs.CONCLUSIONS:
Our results suggest MRTF signalling as a direct target for PFD and implicate that some of the anti-fibrotic effects of PFD may be due to MRTF inhibition in lung fibroblasts.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Fatores de Transcrição
/
Fibrose Pulmonar Idiopática
Limite:
Humans
Idioma:
En
Ano de publicação:
2023
Tipo de documento:
Article