Department of Respiratory and Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
Department of Thoracic Surgery, Zhongnan Hospital of Wuhan University, Wuhan 430060, Hubei Province, China.
Aging (Albany NY). 2023 Oct 9;15(19):10524-10539. doi: 10.18632/aging.205092.
G protein-coupled receptor kinase-2 (GRK2) is involved in TGF-β1-induced activation of lung fibroblasts, which could give rise to the pathogenesis of pulmonary fibrosis. Paroxetine (PRXT) serves as a selective GRK2 inhibitor which is widely used to treat anxiety and depression for several decades. However, whether PRXT could inhibit TGF-β1-induced activation of lung fibroblasts and combat bleomycin-induced pulmonary fibrosis remains unclear. Here, we investigated the effects of PRXT on pulmonary fibrosis in C57/BL6 caused by bleomycin as well as on the activation of murine primary lung fibroblasts stimulated with TGF-β1. The results demonstrated that PRXT markedly improved the pulmonary function and 21-day survival in bleomycin-induced mice. Meanwhile, PRXT significantly decreased collagen deposition, inflammation, and oxidative stress in lung tissues from bleomycin-induced mice. Furthermore, we found that PRXT could inhibit the protein and mRNA expression of GRK2 and Smad3 in lung tissues from bleomycin-induced mice. experiments also PRXT could inhibit cell activation and collagen synthesis in a concentration-dependent manner in TGF-β1-induced lung fibroblasts. In addition, we found that Smad3 overexpression by adenovirus transfection could offset anti-fibrotic and antioxidative effects from PRXT in TGF-β1-induced lung fibroblasts, which showed no effects on the protein expression of GRK2. In conclusion, PRXT mediates the inhibition of GRK2, which further blocks the transcription of Smad3 in TGF-β1-induced lung fibroblasts, providing an attractive therapeutic target for pulmonary fibrosis.
G 蛋白偶联受体激酶 2（GRK2）参与 TGF-β1 诱导的肺成纤维细胞激活，这可能导致肺纤维化的发病机制。帕罗西汀（PRXT）作为一种选择性 GRK2 抑制剂，已被广泛用于治疗焦虑和抑郁数十年。然而，PRXT 是否能抑制 TGF-β1 诱导的肺成纤维细胞激活并对抗博来霉素诱导的肺纤维化尚不清楚。在这里，我们研究了 PRXT 对博来霉素诱导的 C57/BL6 小鼠肺纤维化以及对 TGF-β1 刺激的小鼠原代肺成纤维细胞激活的影响。结果表明，PRXT 显著改善了博来霉素诱导的小鼠的肺功能和 21 天存活率。同时，PRXT 显著减少了博来霉素诱导的小鼠肺组织中的胶原沉积、炎症和氧化应激。此外，我们发现 PRXT 可以抑制博来霉素诱导的小鼠肺组织中 GRK2 和 Smad3 的蛋白和 mRNA 表达。体外实验还发现 PRXT 可以浓度依赖性地抑制 TGF-β1 诱导的肺成纤维细胞的细胞激活和胶原合成。此外，我们发现腺病毒转染过表达 Smad3 可以抵消 PRXT 在 TGF-β1 诱导的肺成纤维细胞中的抗纤维化和抗氧化作用，而对 GRK2 的蛋白表达没有影响。总之，PRXT 介导了 GRK2 的抑制，进一步阻断了 TGF-β1 诱导的肺成纤维细胞中 Smad3 的转录，为肺纤维化提供了一个有吸引力的治疗靶点。
