Dept of Physiology, Michigan State University, East Lansing, MI 48824, USA.
Eur Respir J. 2013 Jul;42(1):198-210. doi: 10.1183/09031936.00015612. Epub 2012 Oct 25.
Alveolar epithelial type II cells, a major source of angiotensin-converting enzyme (ACE)-2 in the adult lung, are normally quiescent but actively proliferate in lung fibrosis and downregulate this protective enzyme. It was, therefore, hypothesised that ACE-2 expression might be related to cell cycle progression. To test this hypothesis, ACE-2 mRNA levels, protein levels and enzymatic activity were examined in fibrotic human lungs and in the alveolar epithelial cell lines A549 and MLE-12 studied at postconfluent (quiescent) versus subconfluent (proliferating) densities. ACE-2 mRNA, immunoreactive protein and enzymatic activity were all high in quiescent cells, but were severely downregulated or absent in actively proliferating cells. Upregulation of the enzyme in cells that were progressing to quiescence was completely inhibited by the transcription blocker actinomycin D or by SP600125, an inhibitor of c-Jun N-terminal kinase (JNK). In lung biopsy specimens obtained from patients with idiopathic pulmonary fibrosis, immunoreactive enzyme was absent in alveolar epithelia that were positive for proliferation markers, but was robustly expressed in alveolar epithelia devoid of proliferation markers. These data explain the loss of ACE-2 in lung fibrosis and demonstrate cell cycle-dependent regulation of this protective enzyme by a JNK-mediated transcriptional mechanism.
肺泡上皮 II 型细胞是成人肺部血管紧张素转换酶（ACE）-2的主要来源，通常处于静止状态，但在肺纤维化中会积极增殖，并下调这种保护酶。因此，有人假设 ACE-2 的表达可能与细胞周期进程有关。为了验证这一假设，研究人员在纤维化的人肺组织以及肺泡上皮细胞系 A549 和 MLE-12 中检测了 ACE-2 的 mRNA 水平、蛋白水平和酶活性，这些细胞分别处于汇合后（静止）和亚汇合（增殖）密度。静止细胞中的 ACE-2 mRNA、免疫反应性蛋白和酶活性均较高，但在活跃增殖的细胞中则严重下调或缺失。用转录抑制剂放线菌素 D 或 c-Jun N 端激酶（JNK）抑制剂 SP600125 完全抑制了正在向静止状态过渡的细胞中酶的上调。在特发性肺纤维化患者的肺活检标本中，增殖标志物阳性的肺泡上皮中缺乏免疫反应性酶，但在没有增殖标志物的肺泡上皮中表达强烈。这些数据解释了肺纤维化中 ACE-2 的丢失，并证明了这种保护性酶通过 JNK 介导的转录机制进行细胞周期依赖性调节。
