Csk/Src/EGFR signaling regulates migration of myofibroblasts and alveolarization
Csk/Src/EGFR signaling regulates migration of myofibroblasts and alveolarization
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DOI：
10.1152/ajplung.00162.2015
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发表时间：
2016-03-15
影响因子：
4.9
通讯作者：
Zhang, Yongjun
中科院分区：
文献类型：
--
作者：
Li, Jianhui;Li, Yahui;Zhang, Yongjun
支气管肺发育不良（BPD）的特征是过早的肺泡发育停滞。孕期暴露于炎症会抑制肺形态发生，从而增加发生BPD的风险。肺泡肌成纤维细胞被认为在肺泡化过程中迁移到间隔尖端并延长次级间隔。在这里，我们发现脂多糖（LPS）破坏了肌成纤维细胞的定向迁移，增加肌动蛋白应力纤维的表达和粘着斑的形成。此外，COOH-末端Src激酶（Csk）活性下调与LPS处理的肌成纤维细胞，而激活的Src或表皮生长因子受体（EGFR）的LPS治疗上调。具体来说，在从羊水内LPS暴露的新生大鼠肺中分离的原代肌成纤维细胞（BPD模型）中也观察到Csk活性降低和Src或EGFR活化增加。进一步的研究表明，EGFR参与了LPS诱导的细胞迁移障碍，Src抑制剂阻断了LPS诱导的EGFR活化或细胞迁移障碍。Csk沉默还导致EGFR活化和细胞迁移受损。此外，我们发现EGFR对肌成纤维细胞迁移的影响是通过RhoA激活介导的。EGFR抑制减轻了肌成纤维细胞的异常定位，改善了产前LPS治疗大鼠的肺泡发育。综上所述，我们的数据表明，Csk/Src/EGFR信号通路在调节肌成纤维细胞的定向迁移中起着关键作用，并可能有助于BPD中肺泡发育的抑制。
Bronchopulmonary dysplasia (BPD) is characterized by premature alveolar developmental arrest. Antenatal exposure to inflammation inhibits lung morphogenesis, thus increasing the risk of developing BPD. Alveolar myofibroblasts are thought to migrate into the septal tips and elongate secondary septa during alveolarization. Here we found lipopolysaccharide (LPS) disrupted the directional migration of myofibroblasts and increased actin stress fiber expression and focal adhesion formation. In addition, COOH-terminal Src kinase (Csk) activity was downregulated in myofibroblasts treated with LPS, while activation of Src or epidermal growth factor receptor (EGFR) was upregulated by LPS treatment. Specifically, decreased Csk activity and increased activation of Src or EGFR was also observed in primary myofibroblasts isolated from newborn rat lungs with intra-amniotic LPS exposure, a model for BPD. Further investigation revealed that EGFR was involved in cell migration impairment induced by LPS, and Src inhibition blocked LPS-induced activation of EGFR or cell migration impairment. Csk silencing also resulted in EGFR activation and cell migration impairment. Besides, we found the effect of EGFR on myofibroblast migration was mediated through RhoA activation. EGFR inhibition alleviated the abnormal localization of myofibroblasts and improved alveolar development in antenatal LPS-treated rats. Taken together, our data suggest that the Csk/Src/EGFR signaling pathway is critically involved in regulating directional migration of myofibroblasts and may contribute to arrested alveolar development in BPD.