一种新型的 BRD4 降解剂 ARV-825 通过细胞衰老溶解和抗纤维化作用来减轻肺纤维化。

A novel BRD4 degrader, ARV-825, attenuates lung fibrosis through senolysis and antifibrotic effect.

机构信息

Department of Respiratory Medicine and Rheumatology, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.

Department of Pathology and Laboratory Medicine, Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan.

出版信息

Respir Investig. 2023 Nov;61(6):781-792. doi: 10.1016/j.resinv.2023.08.003. Epub 2023 Sep 21.

DOI:10.1016/j.resinv.2023.08.003

PMID:37741093

Abstract

BACKGROUND

Recent studies suggest that cellular senescence is related to the pathogenesis of idiopathic pulmonary fibrosis. However, cellular senescence has yet to be targeted therapeutically in clinical practice. ARV825, a recently developed BRD4 degrader, has been reported as a novel senolytic drug. Conversely, it has also been reported that BRD4 regulates the pro-fibrotic gene expression of fibroblasts. Therefore, this study focuses on the senolytic and anti-fibrotic effects of ARV825 and evaluated these effects on lung fibrosis.

METHODS

Lung fibroblasts were induced to senescence through serial passage. The expression of senescence markers and pro-fibrotic markers were determined through quantitative PCR or immunoblot analysis. Lung fibrosis was induced in mice through intratracheal administration of bleomycin. Mice treated with ARV825 underwent histological analysis of lung fibrosis using the Ashcroft score. Total lung collagen was quantified through a hydroxyproline assay. Respiratory mechanics analysis was performed using the flexiVent system.

RESULTS

For senescent cells, ARV825 induced the expression of an apoptosis marker while reducing the expression of BRD4 and senescence markers. On the other hand, for early passage pre-senescent cells, ARV825 reduced the expression of collagen type 1 and α-smooth muscle actin. In an experimental mouse model of lung fibrosis, ARV825 attenuated lung fibrosis and improved lung function. Immunohistochemical staining revealed a significant decrease in the number of senescent alveolar type 2 cells in lung tissue due to ARV825 treatment.

CONCLUSIONS

These results suggest that ARV825 may impact the progressive and irreversible course of fibrotic lung diseases.

摘要

背景

最近的研究表明，细胞衰老与特发性肺纤维化的发病机制有关。然而，在临床实践中，细胞衰老尚未成为治疗的靶点。最近开发的 BRD4 降解剂 ARV825 已被报道为一种新型的衰老细胞溶解药物。相反，也有报道称 BRD4 调节成纤维细胞的促纤维化基因表达。因此，本研究侧重于 ARV825 的衰老细胞溶解和抗纤维化作用，并评估了这些作用对肺纤维化的影响。

方法

通过连续传代诱导肺成纤维细胞衰老。通过定量 PCR 或免疫印迹分析测定衰老标志物和促纤维化标志物的表达。通过气管内给予博来霉素诱导小鼠肺纤维化。用 ARV825 处理的小鼠进行肺纤维化的组织学分析，采用 Ashcroft 评分。羟脯氨酸测定法定量测定总肺胶原蛋白。使用 flexiVent 系统进行呼吸力学分析。

结果

对于衰老细胞，ARV825 诱导凋亡标志物的表达，同时降低 BRD4 和衰老标志物的表达。另一方面，对于早期传代的未衰老细胞，ARV825 降低了胶原 I 型和α-平滑肌肌动蛋白的表达。在肺纤维化的实验小鼠模型中，ARV825 减轻了肺纤维化并改善了肺功能。免疫组织化学染色显示，由于 ARV825 治疗，肺组织中衰老的 II 型肺泡细胞数量显著减少。