Gombedza Farai, Kondeti Vinay, Al-Azzam Nosayba, Koppes Stephanie, Duah Ernest, Patil Prachi, Hexter Madison, Phillips Daniel, Thodeti Charles K, Paruchuri Sailaja
Department of Chemistry, University of Akron, Akron, Ohio, USA; and.
Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
FASEB J. 2017 Apr;31(4):1556-1570. doi: 10.1096/fj.201601045R. Epub 2017 Jan 10.
Contributions of mechanical signals to airway remodeling during asthma are poorly understood. Transient receptor potential vanilloid 4 (TRPV4), a mechanosensitive ion channel, has been implicated in cardiac and pulmonary fibrosis; however, its role in asthma remains elusive. Employing a -induced asthma model, we report here that TRPV4-knockout mice were protected from -induced airway remodeling. Furthermore, lung fibroblasts that were isolated from TRPV4-knockout mice showed diminished differentiation potential compared with wild-type mice. Fibroblasts from asthmatic lung exhibited increased TRPV4 activity and enhanced differentiation potential compared with normal human lung fibroblasts. Of interest, TGF-β1 treatment enhanced TRPV4 activation in a PI3K-dependent manner in normal human lung fibroblasts Mechanistically, TRPV4 modulated matrix remodeling in the lung 2 distinct but dependent pathways: one enhances matrix deposition by fibrotic gene activation, whereas the other slows down matrix degradation by increased plasminogen activator inhibitor 1. Of importance, both pathways are regulated by Rho/myocardin-related transcription factor-A and contribute to fibroblast differentiation and matrix remodeling in the lung. Thus, our results support a unique role for TRPV4 in -induced airway remodeling and warrant further studies in humans for it to be used as a novel therapeutic target in the treatment of asthma.-Gombedza, F., Kondeti, V., Al-Azzam, N., Koppes, S., Duah, E., Patil, P., Hexter, M., Phillips, D., Thodeti, C. K., Paruchuri, S. Mechanosensitive transient receptor potential vanilloid 4 regulates -induced airway remodeling 2 distinct pathways modulating matrix synthesis and degradation.
机械信号在哮喘期间对气道重塑的作用尚不清楚。瞬时受体电位香草酸受体4（TRPV4）是一种机械敏感离子通道，与心脏和肺纤维化有关；然而，其在哮喘中的作用仍不明确。利用一种诱导性哮喘模型，我们在此报告，TRPV4基因敲除小鼠可免受诱导性气道重塑的影响。此外，与野生型小鼠相比，从TRPV4基因敲除小鼠分离出的肺成纤维细胞显示出分化潜能降低。与正常人肺成纤维细胞相比，哮喘肺组织中的成纤维细胞表现出TRPV4活性增加和分化潜能增强。有趣的是，在正常人肺成纤维细胞中，TGF-β1处理以PI3K依赖的方式增强了TRPV4的激活。从机制上讲，TRPV4通过2条不同但相互依赖的途径调节肺中的基质重塑：一条途径通过激活纤维化基因增强基质沉积，而另一条途径通过增加纤溶酶原激活物抑制剂1减缓基质降解。重要的是，这两条途径均受Rho/心肌素相关转录因子-A调节，并有助于肺成纤维细胞的分化和基质重塑。因此，我们的结果支持TRPV4在诱导性气道重塑中的独特作用，并且有必要在人类中进行进一步研究，以便将其用作治疗哮喘的新型治疗靶点。-贡贝德扎，F.，孔德蒂，V.，阿扎姆，N.，科普斯，S.，杜阿，E.，帕蒂尔，P.，赫克斯特，M.，菲利普斯，D.，托德蒂，C.K.，帕鲁丘里，S.机械敏感瞬时受体电位香草酸受体4通过调节基质合成和降解的2条不同途径调节诱导性气道重塑
