c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis
c-Jun N-Terminal Kinase 1 Is Required for the Development of Pulmonary Fibrosis
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DOI：
10.1165/rcmb.2008-0174oc
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发表时间：
2009-04-01
影响因子：
6.4
通讯作者：
Janssen-Heininger, Yvonne M. W.
中科院分区：
文献类型：
--
作者：
Alcorn, John F.;van der Velden, Jos;Janssen-Heininger, Yvonne M. W.
胶原蛋白沉积在多种肺部疾病中被观察到，并且促进胶原蛋白沉积的分子信号传导途径的解开代表了正在进行的研究领域。应激活化蛋白激酶c-Jun N-末端激酶1（JNK 1）被多种细胞应激和环境损伤激活。我们实验室最近的工作证明了JNK 1在上皮向间充质转化中的关键作用。本研究的目的是检查JNK 1参与过敏性气道疾病和间质性肺纤维化模型小鼠的上皮下胶原沉积。激活的JNK略有增强，从小鼠肺进行致敏和挑战与卵清蛋白（Ova），和主要定位磷酸化JNK观察到支气管上皮。虽然缺乏JNK 1的小鼠（JNK 1-/-小鼠）与野生型（WT）小鼠相比显示出增强的肺部炎症和细胞因子产生，但与WT动物相比，JNK 1-/-小鼠对抗原的反应累积较少的上皮下胶原沉积，并显示出促纤维化基因的表达降低。此外，与接受抗原的WT动物相比，JNK 1-/-小鼠支气管肺泡灌洗液中的转化生长因子（TGF）-β 1含量减少。最后，我们证明了缺乏JNK 1的小鼠对TGF-β 1和博来霉素诱导的促纤维化基因表达和肺纤维化具有保护作用。总的来说，这些发现证明了JNK 1在多种纤维化模型中促进胶原沉积的重要要求。
Collagen deposition is observed in a diverse set of pulmonary diseases, and the unraveling of the molecular signaling pathways v that facilitate Collagen deposition represents an ongoing area of investigation. The stress-activated protein kinase, c-Jun N-terminal kinase 1 (JNK1), is activated by a large variety of cellular stresses and environmental insults. Recent work from our laboratory demonstrated the critical role of JNK1 in epithelial to mesenchymal transition. The goal of the present study was to examine the involvement of JNK1 in subepithelial Collagen deposition in mice subjected to models of allergic airways disease and interstitial pulmonary fibrosis. Activation of INK was slightly enhanced in lungs from mice subjected to sensitization and challenge with ovalbumin (Ova), and predominant localization of phospho-JNK was observed in the bronchial epithelium. While mice lacking JNK1 (JNK1-/-mice) displayed enhanced lung inflammation and cytokine production compared with wild-type (WT) mice, JNK1-/- mice accumulated less subepithelial Collagen deposition in response to antigen, and showed decreased expression of profibrotic genes compared with WT animals. Furthermore, transforming growth factor (TGF)-beta 1 content in the bronchoalveolar lavage was diminished in JNK1-/- mice compared with WT animals subjected to antigen. Finally, we demonstrated that mice lacking JNK1 were protected against TGF-beta 1 and bleomycin-induced pro-fibrotic gene expression and pulmonary fibrosis. Collectively, these findings demonstrate an important requirement for JNK1 in promoting Collagen deposition in multiple models of fibrosis.