Shp2 Plays an Important Role in Acute Cigarette Smoke-Mediated Lung Inflammation
Shp2 Plays an Important Role in Acute Cigarette Smoke-Mediated Lung Inflammation
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DOI：
10.4049/jimmunol.1200197
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发表时间：
2012-09-15
影响因子：
4.4
通讯作者：
Ke, Yuehai
中科院分区：
文献类型：
--
作者：
Li, Fen-fen;Shen, Jian;Ke, Yuehai
香烟烟雾 (CS) 是慢性阻塞性肺疾病的主要原因，它含有多种氧化成分，这些成分参与调节含有 Src 同源结构域 2 的蛋白酪氨酸磷酸酶 2 (Shp2) 活性。然而，Shp2 酶在慢性阻塞性肺疾病发病机制中的作用仍不清楚。我们研究了 Shp2 酶在阻断 CS 诱导的肺部炎症中的作用。在体内和体外评估了 Shp2 水平。将小鼠 (C57BL/6) 或肺上皮细胞 (NCI-H292) 暴露于 CS 或香烟烟雾提取物 (CSE) 中以诱导急性损伤和炎症。与对照组相比，吸烟小鼠的肺部显示 Shp2 水平升高。用 CSE 处理肺上皮细胞显示，Shp2 水平升高，且与 IL-8 释放增加相关。选择性抑制或敲低 Shp2 会导致肺上皮细胞响应 CSE 治疗而减少 IL-8 释放。与暴露于CS的野生型小鼠相比，肺上皮细胞中Shp2的选择性抑制或条件敲除减少了暴露于CS的小鼠中IL-8的释放和肺部炎症。体外生化数据将 CSE 介导的 IL-8 释放与 Shp2 调节的表皮生长因子受体/Grb-2 相关结合物/MAPK 信号传导相关联。我们的数据表明 Shp2 在与 CS 介导的炎症相关的病理改变中发挥重要作用。 Shp2 可能是治疗 CS 引起的肺部疾病炎症的潜在靶点。免疫学杂志，2012 年，189：3159-3167。
Cigarette smoke (CS), the major cause of chronic obstructive pulmonary disease, contains a variety of oxidative components that were implicated in the regulation of Src homology domain 2-containing protein tyrosine phosphatase 2 (Shp2) activity. However, the contribution of Shp2 enzyme to chronic obstructive pulmonary disease pathogenesis remains unclear. We investigated the role of Shp2 enzyme in blockading CS-induced pulmonary inflammation. Shp2 levels were assessed in vivo and in vitro. Mice (C57BL/6) or pulmonary epithelial cells (NCI-H292) were exposed to CS or cigarette smoke extract (CSE) to induce acute injury and inflammation. Lungs of smoking mice showed increased levels of Shp2, compared with those of controls. Treatment of lung epithelial cells with CSE showed elevated levels of Shp2 associated with the increased release of IL-8. Selective inhibition or knockdown of Shp2 resulted in decreased IL-8 release in response to CSE treatment in pulmonary epithelial cells. In comparison with CS-exposed wild-type mice, selective inhibition or conditional knockout of Shp2 in lung epithelia reduced IL-8 release and pulmonary inflammation in CS-exposed mice. In vitro biochemical data correlate CSE-mediated IL-8 release with Shp2-regulated epidermal growth factor receptor/Grb-2-associated binders/MAPK signaling. Our data suggest an important role for Shp2 in the pathological alteration associated with CS-mediated inflammation. Shp2 may be a potential target for therapeutic intervention for inflammation in CS-induced pulmonary diseases. The Journal of Immunology, 2012, 189:3159-3167.