Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis.
Persistent localization of activated extracellular signal-regulated kinases (ERK1/2) is epithelial cell-specific in an inhalation model of asbestosis.
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在石棉沉着病吸入模型中，激活的细胞外信号调节激酶 (ERK1/2) 的持续定位具有上皮细胞特异性。
DOI：
10.1016/s0002-9440(10)63867-9
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发表时间：
2003
期刊：
影响因子：
--
通讯作者：
Taatjes,DouglasJ
中科院分区：
文献类型：
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作者：
Cummins,AndrewB;Palmer,Cathy;Mossman,BrookeT;Taatjes,DouglasJ
石棉纤维在体外上调间皮和肺上皮细胞中的细胞外信号调节激酶（ERK1/2）通路，但吸入石棉后肺中活化（即磷酸化）ERK 的细胞类型表达模式和细胞内定位尚不清楚。 C57/BL6 小鼠暴露于 7 mg/m3 空气的青石棉中 5 天和 30 天，分别是上皮细胞增生和纤维化病变发展所需的时间。接触石棉会导致非磷酸化和磷酸化 ERK (p-ERK) 显着增加，在 30 天时最为明显，并且使用细胞角蛋白抗体将其共定位于细支气管和肺泡上皮细胞中。用抗巨噬细胞抗体检测肺泡巨噬细胞不表达p-ERK。 p-ERK 位于暴露于石棉纤维的细支气管和肺泡 II 型上皮细胞的顶端细胞表面，并且在与纤维化病变相关的上皮增生区域最为明显。由于 p-ERK 向细胞核的易位与早期反应基因和转录因子的激活相关，因此使用激光扫描细胞术测定体外肺泡 II 型上皮细胞系暴露于石棉或 ERK 刺激、表皮生长因子或 H2O2 后 p-ERK 的激活和核易位动力学。结果表明，在暴露于石棉的细胞中，p-ERK 的细胞质到核的易位以长期的方式发生。 p-ERK 在膜表面（最初接触石棉纤维的部位）的免疫定位，以及 p-ERK 在纤维发生部位上皮细胞中的慢性激活，与通过 ERK 途径的上皮细胞信号传导有助于肺纤维化发展过程中肺重塑的概念一致。
Asbestos fibers up-regulate the extracellular signal-regulated kinase (ERK1/2) pathway in mesothelial and pulmonary epithelial cells in vitro, but the cell-type expression patterns and intracellular localization of activated, ie, phosphorylated, ERK in the lung after inhalation of asbestos are unclear. C57/BL6 mice were exposed to 7-mg/m3air of crocidolite asbestos for 5 and 30 days, the times required for the development of epithelial cell hyperplasia and fibrotic lesions, respectively. Exposure to asbestos caused striking increases in both unphosphorylated and phosphorylated ERK (p-ERK), which were most marked at 30 days and co-localized in bronchiolar and alveolar epithelial cells using an antibody to cytokeratin. Alveolar macrophages, detected with an anti-macrophage antibody, did not express p-ERK. p-ERK was localized at the apical cell surface of bronchiolar and alveolar type II epithelial cells exposed to asbestos fibers, and was most marked in areas of epithelial hyperplasia in association with fibrotic lesions. Because translocation of p-ERK to the nucleus is associated with activation of early response genes and transcription factors, laser scanning cytometry was used to determine the kinetics of activation and nuclear translocation of p-ERK in an alveolar type II epithelial cell line in vitro after exposure to asbestos or the ERK stimuli, epidermal growth factor, or H2O2. Results showed that cytoplasmic to nuclear translocation of p-ERK occurred in a protracted manner in cells exposed to asbestos. The immunolocalization of p-ERK at the membrane surface, a site of initial exposure to asbestos fibers, and the chronic activation of p-ERK in epithelial cells at sites of fibrogenesis are consistent with the concept that epithelial cell signaling through the ERK pathway contributes to remodeling of the lung during the development of pulmonary fibrosis.