Inhibition of the Arp2/3 complex represses human lung myofibroblast differentiation and attenuates bleomycin-induced pulmonary fibrosis.
CK666
actin
cytoskeleton
fibrosis
Journal
British journal of pharmacology
ISSN: 1476-5381
Titre abrégé: Br J Pharmacol
Pays: England
ID NLM: 7502536
Informations de publication
Date de publication:
01 2022
01 2022
Historique:
revised:
20
05
2021
received:
01
10
2020
accepted:
05
08
2021
pubmed:
29
8
2021
medline:
15
3
2022
entrez:
28
8
2021
Statut:
ppublish
Résumé
The Arp2/3 multiprotein complex regulates branched polymerisation of the actin cytoskeleton and may contribute to collagen synthesis and fibrogenesis in the lung. Expression of Arp2/3 components was assessed in human lung fibroblasts and in the bleomycin-induced pulmonary fibrosis model in mice. The Arp2/3 complex was repressed with the allosteric inhibitor CK666 and with interfering RNAs targeting the ARP2, ARP3 and ARPC2 subunits (siARP2, siARP3 and siARPC2) in CCD-16Lu human lung fibroblasts in vitro. Mice received daily intraperitoneal injections of CK666 from the 7th to the 14th day after tracheal bleomycin instillation. Expression of Arp2/3 complex subunits mRNAs was increased in fibroblasts treated with TGF-β1 and in the lungs of bleomycin-treated mice compared with controls. In vitro, CK666 and siARPC2 inhibited cell growth and TGF-β1-induced α-smooth muscle actin (ACTA2) and collagen-1 (COL1) expression. CK666 also decreased ACTA2 and COL1 expression in unstimulated cells. CK666 reduced Akt phosphorylation and repressed phospho-GSK3β, β-catenin and MRTF-A levels in unstimulated fibroblasts. In vivo, CK666 reduced levels of both procollagen-1 and insoluble collagen in bleomycin-treated mice. Expression of the Arp2/3 complex was increased in profibrotic environments in vitro and in vivo. Inhibition of the Arp2/3 complex repressed ACTA2 and COL1 expression and repressed an Akt/phospho-GSK3β/β-catenin/MRTF-A pathway in lung fibroblasts. CK666 exerted antifibrotic properties in the lung in vivo. Inhibition of the Arp2/3 complex could represent an interesting new therapy for idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases.
Sections du résumé
BACKGROUND AND PURPOSE
The Arp2/3 multiprotein complex regulates branched polymerisation of the actin cytoskeleton and may contribute to collagen synthesis and fibrogenesis in the lung.
EXPERIMENTAL APPROACH
Expression of Arp2/3 components was assessed in human lung fibroblasts and in the bleomycin-induced pulmonary fibrosis model in mice. The Arp2/3 complex was repressed with the allosteric inhibitor CK666 and with interfering RNAs targeting the ARP2, ARP3 and ARPC2 subunits (siARP2, siARP3 and siARPC2) in CCD-16Lu human lung fibroblasts in vitro. Mice received daily intraperitoneal injections of CK666 from the 7th to the 14th day after tracheal bleomycin instillation.
KEY RESULTS
Expression of Arp2/3 complex subunits mRNAs was increased in fibroblasts treated with TGF-β1 and in the lungs of bleomycin-treated mice compared with controls. In vitro, CK666 and siARPC2 inhibited cell growth and TGF-β1-induced α-smooth muscle actin (ACTA2) and collagen-1 (COL1) expression. CK666 also decreased ACTA2 and COL1 expression in unstimulated cells. CK666 reduced Akt phosphorylation and repressed phospho-GSK3β, β-catenin and MRTF-A levels in unstimulated fibroblasts. In vivo, CK666 reduced levels of both procollagen-1 and insoluble collagen in bleomycin-treated mice.
CONCLUSION AND IMPLICATIONS
Expression of the Arp2/3 complex was increased in profibrotic environments in vitro and in vivo. Inhibition of the Arp2/3 complex repressed ACTA2 and COL1 expression and repressed an Akt/phospho-GSK3β/β-catenin/MRTF-A pathway in lung fibroblasts. CK666 exerted antifibrotic properties in the lung in vivo. Inhibition of the Arp2/3 complex could represent an interesting new therapy for idiopathic pulmonary fibrosis and other fibrotic interstitial lung diseases.
Substances chimiques
Actin-Related Protein 2-3 Complex
0
Transforming Growth Factor beta1
0
Bleomycin
11056-06-7
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
125-140Informations de copyright
© 2021 The British Pharmacological Society.
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