Faculty of Biology, Lomonosov Moscow State University, Russian Federation.
Siberian State Medical University, Tomsk, Russian Federation.
Curr Med Chem. 2019;26(3):564-575. doi: 10.2174/0929867324666170619105407.
Myofibroblast activation is a critical process in the pathogenesis of tissue fibrosis accounting for 45% of all deaths. No effective therapies are available for the treatment of fibrotic diseases. We focus our mini-review on recent data showing that cardiotonic steroids (CTS) that are known as potent inhibitors of Na+,K+-ATPase affect myofibroblast differentiation in a cell type-specific manner. In cultured human lung fibroblasts (HLF), epithelial cells, and cancer-associated fibroblasts, CTS blocked myofibroblast differentiation triggered by profibrotic cytokine TGF-β. In contrast, in the absence of TGF-β, CTS augmented myofibroblast differentiation of cultured cardiac fibroblasts. The cell type-specific action of CTS in myofibroblast differentiation is consistent with data obtained in in vivo studies. Thus, infusion of ouabain via osmotic mini-pumps attenuated the development of lung fibrosis in bleomycintreated mice, whereas marinobufagenin stimulated renal and cardiac fibrosis in rats with experimental renal injury. In TGF-β-treated HLF, suppression of myofibroblast differentiation by ouabain is mediated by elevation of the [Na+]i/[K+]i ratio and is accompanied by upregulation of cyclooxygenase COX-2 and downregulation of TGF-β receptor TGFBR2. Augmented expression of COX-2 is abolished by inhibition of Na+/Ca2+ exchanger, suggesting a key role of [Ca2+]i-mediated signaling. What is the relative impact in tissue fibrosis of [Na+]i,[K+]iindependent signaling documented in several types of CTS-treated cells? Do the different conformational transitions of Na+,K+-ATPase α1 subunit in the presence of ouabain and marinobufagenin contribute to their distinct involvement in myofibroblast differentiation? Additional experiments should be done to answer these questions and to develop novel pharmacological approaches for the treatment of fibrosis-related disorders.
肌成纤维细胞激活是组织纤维化发病机制中的一个关键过程，占所有死亡人数的 45%。目前尚无有效的治疗纤维化疾病的方法。我们的小型综述重点介绍了最近的数据，这些数据表明，已知为强效 Na+，K+-ATP 酶抑制剂的强心甾类化合物（CTS）以细胞类型特异性的方式影响肌成纤维细胞的分化。在培养的人肺成纤维细胞（HLF）、上皮细胞和癌相关成纤维细胞中，CTS 阻断了由促纤维化细胞因子 TGF-β触发的肌成纤维细胞分化。相比之下，在没有 TGF-β的情况下，CTS 增强了培养的心脏成纤维细胞的肌成纤维细胞分化。CTS 在肌成纤维细胞分化中的细胞类型特异性作用与体内研究中获得的数据一致。因此，通过渗透压微型泵输注哇巴因可减轻博来霉素治疗的小鼠肺纤维化的发展，而马利诺巴芬在实验性肾损伤大鼠中刺激肾和心脏纤维化。在 TGF-β处理的 HLF 中，哇巴因抑制肌成纤维细胞分化是通过升高[Na+]i/[K+]i 比值介导的，并伴有环氧化酶 COX-2 的上调和 TGF-β受体 TGFBR2 的下调。Na+/Ca2+交换抑制剂的抑制作用消除了 COX-2 的增强表达，表明[Ca2+]i 介导的信号转导起着关键作用。在几种类型的 CTS 处理细胞中记录到的[Na+]i，[K+]i 独立信号对组织纤维化的相对影响是什么？哇巴因和马利诺巴芬存在时 Na+，K+-ATP 酶α1 亚基的不同构象转变是否有助于它们在肌成纤维细胞分化中的不同参与？应进行额外的实验来回答这些问题，并为纤维化相关疾病的治疗开发新的药理学方法。
