In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis
In vitro and in vivo evidence for an inflammatory role of the calcium channel TRPV4 in lung epithelium: Potential involvement in cystic fibrosis
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DOI：
10.1152/ajplung.00442.2015
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发表时间：
2016-09-01
影响因子：
4.9
通讯作者：
Si-Tahar, Mustapha
中科院分区：
文献类型：
--
作者：
Henry, Clemence O.;Dalloneau, Emilie;Si-Tahar, Mustapha
囊性纤维化（CF）是一种与慢性严重肺部炎症相关的遗传性疾病，可导致过早死亡。为了开发创新的抗炎治疗方法，我们需要表征有助于肺部炎症机制的新细胞和分子组分。在这里，我们专注于“瞬时受体电位香草酸-4”（TRPV 4），一种非选择性钙通道的潜在作用。我们使用体外和体内方法来证明在气道上皮细胞中表达的TRPV 4触发主要促炎介质如趋化因子和生物活性脂质的分泌，以及肺组织中中性粒细胞的募集。我们描述了胞浆磷脂酶A（2）、MAPK和NF-κ B在TRPV 4依赖性信号传导中的作用。我们还表明，5，6-，8，9-，11，12-和14，15-环氧二十碳三烯酸，即，四种天然的基于脂质的TRPV 4激动剂存在于CF患者的痰中。此外，TRPV 4诱导的钙动员和炎症反应在囊性纤维化跨膜传导调节因子缺陷的细胞和动物模型中增强，表明TRPV 4是开发用于诸如CF的疾病的新抗炎治疗的有希望的靶点。
Cystic fibrosis (CF) is an inherited disease associated with chronic severe lung inflammation, leading to premature death. To develop innovative anti-inflammatory treatments, we need to characterize new cellular and molecular components contributing to the mechanisms of lung inflammation. Here, we focused on the potential role of "transient receptor potential vanilloid-4" (TRPV4), a nonselective calcium channel. We used both in vitro and in vivo approaches to demonstrate that TRPV4 expressed in airway epithelial cells triggers the secretion of major proinflammatory mediators such as chemokines and biologically active lipids, as well as a neutrophil recruitment in lung tissues. We characterized the contribution of cytosolic phospholipase A(2), MAPKs, and NF-kappa B in TRPV4-dependent signaling. We also showed that 5,6-, 8,9-, 11,12-, and 14,15-epoxyeicosatrienoic acids, i.e., four natural lipid-based TRPV4 agonists, are present in expectorations of CF patients. Also, TRPV4-induced calcium mobilization and inflammatory responses were enhanced in cystic fibrosis transmembrane conductance regulator-deficient cellular and animal models, suggesting that TRPV4 is a promising target for the development of new anti-inflammatory treatments for diseases such as CF.