Absence of c-Jun NH2-terminal kinase 1 protects against house dust mite-induced pulmonary remodeling but not airway hyperresponsiveness and inflammation

作者：van der Velden, Jos L. J.; Hoffman, Sidra M.; Alcorn, John F.; Tully, Jane E.; Chapman, David G.; Lahue, Karolyn G.; Guala, Amy S.; Lundblad, Lennart K. A.; Aliyeva, Minara; Daphtary, Nirav; Irvin, Charles G.; Janssen-Heininger, Yvonne M. W.^*

来源：American Journal of Physiology - Lung Cellular and Molecular Physiology, 2014, 306(9): L866-L875.

DOI：10.1152/ajplung.00153.2013

• lung
• epithelium
• fibrosis
• airway
• epithelial-to-mesenchymal transition

Chronic allergic asthma leads to airway remodeling and subepithelial fibrosis via mechanisms not fully understood. Airway remodeling is amplified by profibrotic mediators, such as transforming growth factor-beta 1 (TGF-beta 1), which plays a cardinal role in various models of fibrosis. We recently have identified a critical role for c-Jun-NH2-terminalkinase (JNK)1 in augmenting the profibrotic effects of TGF-beta 1, linked to epithelial-to-mesenchymal transition of airway epithelial cells. To examine the role of JNK1 in house dust mite (HDM)-induced airway remodeling, we induced allergic airway inflammation in wildtype (WT) and JNK1-/- mice by intranasal administration of HDM extract. WT and JNK1-/- mice were sensitized with intranasal aspirations of HDM extract for 15 days over 3 wk. HDM caused similar increases in airway hyperresponsiveness, mucus metaplasia, and airway inflammation in WT and JNK1-/- mice. In addition, the profibrotic cytokine TGF-beta 1 and phosphorylation of Smad3 were equally increased in WT and JNK1-/- mice. In contrast, increases in collagen content in lung tissue induced by HDM were significantly attenuated in JNK1-/- mice compared with WT controls. Furthermore HDM-induced increases of alpha-smooth muscle actin (alpha-SMA) protein and mRNA expression as well as the mesenchymal markers high-mobility group AT-hook 2 and collagen1A1 in WT mice were attenuated in JNK1-/- mice. The let-7 family of microRNAs has previously been linked to fibrosis. HDM exposure in WT mice and primary lung epithelial cells resulted in striking decreases in let-7g miRNA that were not observed in mice or primary lung epithelial cells lacking JNK1-/- mice. Overexpression of let-7g in lung epithelial cells reversed the HDM-induced increases in alpha-SMA. Collectively, these findings demonstrate an important requirement for JNK1 in promoting HDM-induced fibrotic airway remodeling.

• 出版日期2014-5