Involvement of c-Jun N-Terminal Kinase in TNF-α-Driven Remodeling
Involvement of c-Jun N-Terminal Kinase in TNF-α-Driven Remodeling
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DOI：
10.1165/rcmb.2015-0195oc
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发表时间：
2017-03-01
影响因子：
6.4
通讯作者：
Dentener, Mieke A.
中科院分区：
文献类型：
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作者：
Eurlings, Irene M. J.;Reynaert, Niki L.;Dentener, Mieke A.
慢性阻塞性肺疾病（COPD）的肺组织重塑以气道壁增厚和/或肺气肿为特征。尽管支气管和肺泡隔室在功能上是独立的实体，但我们最近发现，肺泡和小气道壁的基质成分发生了类似的变化，包括弹性蛋白含量降低，胶原蛋白和透明质酸含量增加。在测试的几种动物模型中，表面活性剂蛋白C (SPC)- tnf - α小鼠在肺泡和气道壁中表现出与我们在COPD患者中观察到的相似的重塑。上皮细胞能够经历表型转变，获得间质特性，这一过程涉及到c-Jun n -末端激酶（JNK）信号传导。因此，我们假设tnf - α诱导jnk依赖性上皮可塑性，这有助于肺基质重塑。为此，我们在A549、BEAS2B和原代支气管上皮细胞中评估了tnf - α诱导表型转移的能力，并在spf - tnf - α小鼠中研究了表型标记物。在体内和体外，间充质细胞表型标志物均升高，如波形蛋白、纤溶酶原激活物抑制剂-1、胶原蛋白和基质金属蛋白酶的表达。同时，上皮标志物E-cadherin、角蛋白7和角蛋白18的表达减弱。JNK的药理学抑制剂在体外减弱了这种表型转变，证明JNK信号参与了这一过程。有趣的是，JNK信号的激活在spc - tnf - α小鼠和COPD患者的肺中也明显存在。总之，这些数据显示了tnf - α在体外诱导表型转移中的作用，导致胶原生成增加和弹性蛋白降解基质金属蛋白酶的表达，并为tnf - α - jnk轴参与细胞外基质重塑提供了证据。
Lung tissue remodeling in chronic obstructive pulmonary disease (COPD) is characterized by airway wall thickening and/or emphysema. Although the bronchial and alveolar compartments are functionally independent entities, we recently showed comparable alterations in matrix composition comprised of decreased elastin content and increased collagen and hyaluronan contents of alveolar and small airway walls. Out of several animal models tested, surfactant protein C (SPC)-TNF-alpha mice showed remodeling in alveolar and airway walls similar to what we observed in patients with COPD. Epithelial cells are able to undergo a phenotypic shift, gaining mesenchymal properties, a process in which c-Jun N-terminal kinase (JNK) signaling is involved. Therefore, we hypothesized that TNF-alpha induces JNK-dependent epithelial plasticity, which contributes to lung matrix remodeling. To this end, the ability of TNF-alpha to induce a phenotypic shift was assessed in A549, BEAS2B, and primary bronchial epithelial cells, and phenotypic markers were studied in SPC-TNF-alpha mice. Phenotypic markers of mesenchymal cells were elevated both in vitro and in vivo, as shown by the expression of vimentin, plasminogen activator inhibitor-1, collagen, and matrix metalloproteinases. Concurrently, the expression of the epithelial markers, E-cadherin and keratin 7 and 18, was attenuated. A pharmacological inhibitor of JNK attenuated this phenotypic shift in vitro, demonstrating involvement of JNK signaling in this process. Interestingly, activation of JNK signaling was also clearly present in lungs of SPC-TNF-alpha mice and patients with COPD. Together, these data show a role for TNF-alpha in the induction of a phenotypic shift in vitro, resulting in increased collagen production and the expression of elastin-degrading matrix metalloproteinases, and provide evidence for involvement of the TNF-alpha-JNK axis in extracellular matrix remodeling.