Laboratory of Clinical Pharmaceutical Science, Kobe Pharmaceutical University, 4-19-1 Motoyamakita, Higashinada, Kobe, 658-8558, Japan.
Division of Cardiovascular Medicine, Department of Internal Medicine, Kobe University Graduate School of Medicine, 7-5-1 Kusunoki, Chuo, Kobe, 650-0017, Japan.
Kobe J Med Sci. 2021 Nov 2;67(2):E61-E70.
Initially, endothelin (ET)-2 was described as an endothelium-derived vasoconstrictor. However, accumulating evidence suggests the involvement of ET-2 in non-cardiovascular physiology and disease pathophysiology. The deficiency of ET-2 in mice can be lethal, and such mice exhibit a distinct developmental abnormality in the lungs. Nonetheless, the definite role of ET-2 in the lungs remains unclear. The ET-2 isoform, ET-1, promotes pulmonary fibrosis in mice. Although endothelin receptor antagonists (ERAs) show improvements in bleomycin-induced pulmonary fibrosis in mouse models, clinical trials examining ERAs for pulmonary fibrosis treatment have been unsuccessful, even showing harmful effects in patients. We hypothesized that ET-2, which activates the same receptor as ET-1, plays a distinct role in pulmonary fibrosis. In this study, we showed that ET-2 is expressed in the lung epithelium, and ET-2 deletion in epithelial cells of mice results in the exacerbation of bleomycin-induced pulmonary fibrosis. ET-2 knockdown in lung epithelial cell lines resulted in increased apoptosis mediated via oxidative stress induction. In contrast to the effects of ET-1, which induced fibroblast activation, ET-2 hampered fibroblast activation in primary mouse lung fibroblast cells by inhibiting the TGF-β-SMAD2/3 pathway. Our results demonstrated the divergent roles of ET-1 and ET-2 in pulmonary fibrosis pathophysiology and suggested that ET-2, expressed in epithelial cells, exerts protective effects against the development of pulmonary fibrosis in mice.
最初，内皮素（ET）-2 被描述为一种内皮衍生的血管收缩剂。然而，越来越多的证据表明 ET-2 参与了非心血管生理学和疾病病理生理学。ET-2 缺乏的小鼠可能会致命，并且这些小鼠的肺部会出现明显的发育异常。尽管如此，ET-2 在肺部的确切作用仍不清楚。ET-2 同工型 ET-1 可促进小鼠的肺纤维化。尽管内皮素受体拮抗剂（ERAs）在小鼠模型中对博来霉素诱导的肺纤维化显示出改善作用，但检查 ERAs 治疗肺纤维化的临床试验均未成功，甚至在患者中显示出有害作用。我们假设激活与 ET-1 相同受体的 ET-2 在肺纤维化中发挥独特作用。在这项研究中，我们表明 ET-2 在肺上皮细胞中表达，并且 ET-2 在小鼠上皮细胞中的缺失会导致博来霉素诱导的肺纤维化加重。肺上皮细胞系中 ET-2 的敲低导致通过诱导氧化应激导致的细胞凋亡增加。与 ET-1 诱导成纤维细胞激活的作用相反，ET-2 通过抑制 TGF-β-SMAD2/3 途径阻碍原代小鼠肺成纤维细胞中的成纤维细胞激活。我们的结果表明 ET-1 和 ET-2 在肺纤维化病理生理学中发挥了不同的作用，并表明在小鼠中表达于上皮细胞的 ET-2 对肺纤维化的发展具有保护作用。
