PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity.
PLAGL2 expression-induced lung epithelium damages at bronchiolar alveolar duct junction in emphysema: bNip3- and SP-C-associated cell death/injury activity.
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DOI：
10.1152/ajplung.00144.2009
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发表时间：
2009-07
期刊：
影响因子：
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通讯作者：
Yih-Sheng Yang;Meng-Chun W. Yang;Yuhong Guo;O. W. Williams;J. Weissler
中科院分区：
文献类型：
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作者：
Yih-Sheng Yang;Meng-Chun W. Yang;Yuhong Guo;O. W. Williams;J. Weissler
肺气肿和支气管炎是慢性阻塞性肺疾病（COPD）的主要组成部分。多形性腺瘤基因样蛋白2（PLAGL 2）是一种锌指DNA结合蛋白，是表面活性蛋白C（SP-C）启动子的转录因子。使用可诱导的转基因小鼠模型，PLAGL 2和SP-C异位表达于终末细支气管的肺上皮细胞，包括支气管肺泡管连接处（BADJ），在正常条件下只有少数细胞表达这两种基因。异位PLAGL 2也在诱导小鼠肺泡II型细胞中表达。PLAGL 2的过表达与成年小鼠远端气道中的气隙扩大的发展相关。在肺气肿的病变中发现有缺陷的肺泡隔和降解的气道碎片，表明慢性气道破坏。雌性小鼠对PLAGL 2过表达的影响特别敏感，与雄性小鼠相比具有更显著的肺气肿变化。此外，对小鼠呼吸系统力学的分析表明，PLAGL 2的诱导导致呼吸系统顺应性的显著增加。TdT介导的dUTP缺口末端标记（TUNEL）和caspase-3分析表明，在肺气肿病变以及在BADJ的上皮细胞凋亡活性增加。我们的研究结果表明，增加细胞损伤和/或死亡可能直接引起的PLAGL 2下游基因，bNip 3，一个凋亡前分子，与Bcl-2二聚体的上调，或间接的异常表达的SP-C诱导的内质网应激上皮细胞。最后，肺泡上皮细胞中PLAGL 2表达增加与COPD患者肺气肿的发展相关。总之，我们来自动物和人类研究的数据支持PLAGL 2在肺气肿中的新致病作用，这是严重COPD的一个关键方面。
Emphysema and bronchitis are major components of chronic obstructive pulmonary disease (COPD). Pleomorphic adenoma gene like-2 (PLAGL2), a zinc finger DNA-binding protein, is a transcription factor of the surfactant protein C (SP-C) promoter. Using an inducible transgenic mouse model, PLAGL2 and SP-C were ectopically expressed in lung epithelial cells of terminal bronchiole including the bronchoalveolar duct junction (BADJ), where only few cells express both genes under normal conditions. Ectopic PLAGL2 was also expressed in alveolar type II cells of induced mice. The overexpression of PLAGL2 was associated with the development of air space enlargement in the distal airways of adult mice. Defective alveolar septa and degraded airway fragments were found in the lesions of emphysematous lungs, indicating chronic airway destruction. Female mice were particularly sensitive to the effects of PLAGL2 overexpression with more dramatic emphysematous changes compared with male mice. In addition, analysis of the respiratory system mechanics in the mice indicated that the induction of PLAGL2 resulted in a significant increase in respiratory system compliance. Both TdT-mediated dUTP nick end labeling (TUNEL) and caspase-3 analyses showed that apoptotic activity was increased in epithelial cells within the emphysematous lesions as well as at the BADJ. Our results indicate that increased cell injury and/or death could be caused directly by the upregulation of PLAGL2 downstream gene, bNip3, a preapoptotic molecule that dimerizes with Bcl-2, or indirectly by the aberrant expression of SP-C-induced endoplasmic reticulum stress in epithelial cells. Finally, increased expression of PLAGL2 in alveolar epithelial cells correlated with the development of emphysema in the lung of COPD patients. In summary, our data from both animal and human studies support a novel pathogenic role of PLAGL2 in pulmonary emphysema, a critical aspect of severe COPD.