Centre d'Etudes des Pathologies Respiratoires, Inserm UMR1100, Tours, France.
Université de Tours, Tours, France.
Br J Pharmacol. 2022 Jan;179(1):125-140. doi: 10.1111/bph.15675. Epub 2021 Nov 15.
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.
Arp2/3 多蛋白复合物调节肌动蛋白细胞骨架的分支聚合，可能有助于肺中胶原的合成和纤维化。
评估了人肺成纤维细胞中 Arp2/3 成分的表达，并在博来霉素诱导的肺纤维化模型小鼠中进行了研究。在体外，用变构抑制剂 CK666 和针对 ARP2、ARP3 和 ARPC2 亚基的干扰 RNA（siARP2、siARP3 和 siARPC2）抑制 CCD-16Lu 人肺成纤维细胞中的 Arp2/3 复合物。小鼠在气管内博来霉素滴注后的第 7 至 14 天每天接受腹腔注射 CK666。
与对照组相比，TGF-β1 处理的成纤维细胞和博来霉素处理的小鼠肺中 Arp2/3 复合物亚基 mRNA 的表达增加。在体外，CK666 和 siARPC2 抑制细胞生长和 TGF-β1 诱导的α-平滑肌肌动蛋白（ACTA2）和胶原-1（COL1）表达。CK666 还降低了未刺激细胞中的 ACTA2 和 COL1 表达。CK666 降低了未刺激成纤维细胞中 Akt 的磷酸化，并抑制了磷酸化 GSK3β、β-catenin 和 MRTF-A 的水平。在体内，CK666 降低了博来霉素处理的小鼠中前胶原-1 和不溶性胶原的水平。
Arp2/3 复合物在体外和体内的致纤维化环境中表达增加。Arp2/3 复合物的抑制抑制了 ACTA2 和 COL1 的表达，并抑制了肺成纤维细胞中的 Akt/磷酸化 GSK3β/β-catenin/MRTF-A 途径。CK666 在体内对肺具有抗纤维化作用。Arp2/3 复合物的抑制可能成为特发性肺纤维化和其他纤维性间质性肺疾病的一种新的治疗方法。
