Targeting the MEK1 cascade in lung epithelium inhibits proliferation and fibrogenesis by asbestos.
Targeting the MEK1 cascade in lung epithelium inhibits proliferation and fibrogenesis by asbestos.
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靶向肺上皮中的 MEK1 级联可抑制石棉的增殖和纤维形成。
DOI：
10.1165/rcmb.2007-0382oc
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发表时间：
2008
影响因子：
6.4
通讯作者：
Mossman,BrookeT
中科院分区：
文献类型：
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作者：
Manning,ChristopherB;Sabo-Attwood,Tara;Robledo,RaymondF;Macpherson,MaximilianB;Rincón,Mercedes;Vacek,Pamela;Hemenway,David;Taatjes,DouglasJ;Lee,PattyJ;Mossman,BrookeT
吸入石棉后，细胞外信号调节激酶 1 和 2 (ERK1/2) 被磷酸化。阻断肺上皮信号通路的效果尚不清楚。表达针对肺上皮的显性失活丝裂原激活蛋白激酶激酶 1 (dnMEK1)（即 ERK1/2 磷酸化所需的上游激酶）的暴露于石棉的转基因小鼠表现出肺的形态和分子变化。转基因阳性 (Tg+)（即 dnMEK1）和转基因阴性（Tg−）同窝小鼠暴露于青石棉 2、4、9 和 32 天或保持在清洁空气中（假对照组）。使用激光捕获显微切割分离远端细支气管上皮，并分析 mRNA 的增殖分子标记和 Clara 细胞分泌蛋白 (CCSP)。分析肺和支气管肺泡灌洗液的炎症和增殖变化以及纤维发生的分子标记。暴露于石棉的野生型小鼠的远端细支气管上皮在第 2 天显示出 c-fosat 表达增加。在石棉暴露的 Tg+ 小鼠中，组蛋白 H3 mRNA 水平升高和 Ki-67 标记的增殖细支气管上皮细胞数量在第 4 天时下降。 32 天时，暴露于石棉的 Tg+ 小鼠肺中通常由 Clara 细胞组成的远端细支气管表现出非复制性纤毛和粘蛋白分泌细胞，并且 CCSP mRNA 水平降低。在石棉暴露的 Tg− 小鼠的肺匀浆中，与纤维形成相关的基因表达（原胶原 3-a-1、原胶原 1-a-1 和 IL-6）也增加，但在石棉暴露的 Tg+ 小鼠中减少。这些结果表明 MEK1 信号传导在中毒性损伤后上皮细胞增殖和肺重塑中发挥着关键作用。
The extracellular signal–regulated kinases 1 and 2 (ERK1/2) are phosphorylated after inhalation of asbestos. The effect of blocking this signaling pathway in lung epithelium is unclear. Asbestos-exposed transgenic mice expressing a dominant-negative mitogen-activated protein kinase kinase-1 (dnMEK1) (i.e., the upstream kinase necessary for phosphorylation of ERK1/2) targeted to lung epithelium exhibited morphologic and molecular changes in lung. Transgene-positive (Tg+) (i.e., dnMEK1) and transgene-negative (Tg−) littermates were exposed to crocidolite asbestos for 2, 4, 9, and 32 days or maintained in clean air (sham controls). Distal bronchiolar epithelium was isolated using laser capture microdissection and mRNA analyzed for molecular markers of proliferation and Clara cell secretory protein (CCSP). Lungs and bronchoalveolar lavage fluids were analyzed for inflammatory and proliferative changes and molecular markers of fibrogenesis. Distal bronchiolar epithelium of asbestos-exposed wild-type mice showed increased expression ofc-fosat 2 days. Elevated mRNA levels ofhistone H3and numbers of Ki-67–labeled proliferating bronchiolar epithelial cells were decreased at 4 days in asbestos-exposed Tg+ mice. At 32 days, distal bronchioles normally composed of Clara cells in asbestos-exposed Tg+ mouse lungs exhibited nonreplicating ciliated and mucin-secreting cells as well as decreased mRNA levels of CCSP. Gene expression (procollagen 3-a-1,procollagen 1-a-1, andIL-6)linked to fibrogenesis was also increased in lung homogenates of asbestos-exposed Tg− mice, but reduced in asbestos-exposed Tg+ mice. These results suggest a critical role of MEK1 signaling in epithelial cell proliferation and lung remodeling after toxic injury.