PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation
PLK1 Inhibition alleviates transplant-associated obliterative bronchiolitis by suppressing myofibroblast differentiation
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PLK1 抑制通过抑制肌成纤维细胞分化减轻移植相关的闭塞性细支气管炎
作者：
Yu Jizhang;Xu Heng;Cui Jikai;Chen Shanshan;Zhang Hao;Zou Yanqiang;Zhao Jing;Le Sheng;Jiang Lang;Chen Zhang;Liu Hao;Zhang Dan;Xia Jiahong;Wu Jie
由纤维化引起的慢性同种异体移植物功能障碍（CAD）是肺移植患者长期生存的主要限制因素。肌成纤维细胞促进包括肺在内的多个器官的纤维化。在这项研究中，我们确定PLK1是肌成纤维细胞分化的启动子，并研究了其抑制缓解CAD期间移植相关的闭塞性细支气管炎（OB）的机制。利用小鼠异位气管移植模型进行的高通量生物信息学分析和实验显示，与对照组相比，PLK1在CAD移植中表达上调，抑制PLK1可缓解体内OB。体外抑制PLK1可降低特异性肌成纤维细胞分化标志物α-平滑肌肌动蛋白（α-SMA）的表达，降低MEK和ERK的磷酸化水平。重要的是，我们在人类原代成纤维细胞中观察到类似的现象。因此，我们的研究结果突出了PLK1作为一个有希望的治疗靶点，通过抑制TGF-β1介导的肌成纤维细胞分化来缓解移植相关的OB。
Chronic allograft dysfunction (CAD) resulting from fibrosis is the major limiting factor for long-term survival of lung transplant patients. Myofibroblasts promote fibrosis in multiple organs, including the lungs. In this study, we identified PLK1 as a promoter of myofibroblast differentiation and investigated the mechanism by which its inhibition alleviates transplant-associated obliterative bronchiolitis (OB) during CAD. High-throughput bioinformatic analyses and experiments using the murine heterotopic tracheal transplantation model revealed that PLK1 is upregulated in grafts undergoing CAD as compared with controls, and that inhibiting PLK1 alleviates OB in vivo. Inhibition of PLK1 in vitro reduced expression of the specific myofibroblast differentiation marker α-smooth muscle actin (α-SMA) and decreased phosphorylation of both MEK and ERK. Importantly, we observed a similar phenomenon in human primary fibroblasts. Our results thus highlight PLK1 as a promising therapeutic target for alleviating transplant-associated OB through suppression of TGF-β1-mediated myofibroblast differentiation.