GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium
GP130-STAT3 regulates epithelial cell migration and is required for repair of the bronchiolar epithelium
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DOI：
10.2353/ajpath.2008.071052
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发表时间：
2008-06-01
影响因子：
6
通讯作者：
Whitsett, Jeffrey A.
中科院分区：
文献类型：
--
作者：
Kida, Hiroshi;Mucenski, Michael L.;Whitsett, Jeffrey A.
损伤后，细支气管细胞经历迅速的鳞状化生，随后是复杂的柱状上皮的增殖和重建，这是正常呼吸道的特征。调节细支气管上皮修复的机制对于理解与气道重塑相关的急、慢性肺部疾病的发病机制具有重要意义。本研究旨在确定gp130-STAT3信号通路在细支气管上皮修复中的作用。体内转基因小鼠肺上皮细胞中信号转导和转录激活因子3(STAT3)和糖蛋白130(Gp130)被选择性缺失，分别产生STAT3(Delta/Delta)和gp130(Delta/Delta)小鼠。以非纤毛呼吸道上皮细胞(Clara细胞)的毒物--萘诱导成年小鼠呼吸道损伤。在对照(STAT3(FLOX/FLOX))小鼠中，在萘介导的损伤后，细支气管壁上皮细胞发生核STAT3染色。对照组小鼠细支气管壁在13天内几乎完全修复，而STAT3(Delta/Delta)或gp130(Delta/Delta)组小鼠外周细支气管壁细胞形态、细胞密度及纤毛和非纤毛细胞形态均未见恢复。在体外修复过程中，显性负性STAT3的表达抑制了呼吸道上皮细胞的迁移；野生型STAT3的表达激活了这种迁移。在本研究中，我们展示了gp130-STAT3信号以细胞自主的方式发挥功能，以恢复损伤后细支气管上皮修复所需的细胞形状和数量。
Following injury, bronchiolar cells undergo rapid squamous metaplasia, followed by proliferation and re-establishment of the complex columnar epithelium that is characteristic of the normal airway. Mechanisms that regulate the repair of bronchiolar epithelium are of considerable relevance for understanding the pathogenesis of both acute and chronic lung diseases associated with airway remodeling. This study was designed to identify the role of the GP130-STAT3 signaling pathway during repair of the bronchiolar epithelium. STAT3 (signal transducer and activator of transcription 3) and GP130 (glycoprotein 130) were each selectively deleted from the pulmonary epithelial cells of transgenic mice in vivo, producing Stat3(Delta/Delta) and Gp130(Delta/Delta) mice, respectively. Airway injury was induced in adult mice by administration of naphthalene, a toxicant of nonciliated respiratory epithelial cells (Clara cells). Nuclear STAT3 staining was induced in bronchiolar epithelial cells following naphthalene-mediated injury in control (Stat3(flox/flox)) mice. Whereas nearly complete repair of the bronchiolar epithelium was observed in control mice within 13 days, restoration of cell shape, cell density, and the pattern of ciliated and nonciliated cells did not occur in the peripheral bronchioles of either Stat3(Delta/Delta) or GP130(Delta/Delta) mice. Expression of dominant-negative STAT3 inhibited airway epithelial cell migration during repair in vitro; wild-type STAT3 expression activated such migration. In the present study, we show that GP130-STAT3 signaling functions in a cell-autonomous manner to restore cell shape and numbers required for repair of the bronchiolar epithelium following injury.