TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.
TRPV4-mediated calcium influx into human bronchial epithelia upon exposure to diesel exhaust particles.
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DOI：
10.1289/ehp.1002807
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发表时间：
2011-06
影响因子：
10.4
通讯作者：
Liedtke W
中科院分区：
文献类型：
--
作者：
Li J;Kanju P;Patterson M;Chew WL;Cho SH;Gilmour I;Oliver T;Yasuda R;Ghio A;Simon SA;Liedtke W
人类呼吸道上皮在气道粘液纤毛清除和屏障功能中发挥作用，并且最近与感觉功能有关。我们研究了慢性阻塞性肺病 (COPD) 发病机制与柴油机尾气颗粒 (DEP) 引起的 Ca2+ 流入人体气道上皮细胞的分子机制之间的联系。使用人呼吸道上皮 (HRE) 细胞的原代培养物，我们确定这些细胞具有蛋白水解信号传导机制，通过蛋白酶激活受体 2 (PAR-2) 激活 Ca2+ 渗透性 TRPV4，从而导致人类呼吸道疾病增强基质金属蛋白酶 1 (MMP-1) 的激活，这是一种由柴油机尾气颗粒 (DEP) 引发的信号级联反应， 全球相关的空气污染物。此外，我们观察了人气道上皮细胞中 PAR-2、TRPV4 和磷脂酶-Cβ3 的纤毛表达及其 DEP 增强的蛋白质-蛋白质复合物形成。我们还发现，慢性阻塞性肺疾病 (COPD) 易感性 TRPV4P19S 变异会增强 Ca2+ 流入和 MMP 1 激活，从而在人为空气污染和人类气道疾病之间提供了机制联系。 DEP 通过 TRPV4 引起持久的 Ca2+ 流入，并通过易患 COPD 的人类遗传多态性 TRPV4P19S 增强。这种机制重新编程了人类气道中适应不良的炎症和细胞外基质重塑反应。人类呼吸道上皮细胞中从 PAR-2 到 TRPV4 的空气污染响应纤毛信号转导的新概念将加速合理的靶向治疗，可能通过吸入途径。
Human respiratory epithelia function in airway mucociliary clearance and barrier function and have recently been implicated in sensory functions. We investigated a link between chronic obstructive pulmonary disease (COPD) pathogenesis and molecular mechanisms underlying Ca2+ influx into human airway epithelia elicited by diesel exhaust particles (DEP). Using primary cultures of human respiratory epithelial (HRE) cells, we determined that these cells possess proteolytic signaling machinery, whereby proteinase-activated receptor-2 (PAR-2) activates Ca2+-permeable TRPV4, which leads to activation of human respiratory disease–enhancing matrix metalloproteinase-1 (MMP-1), a signaling cascade initiated by diesel exhaust particles (DEP), a globally relevant air pollutant. Moreover, we observed ciliary expression of PAR-2, TRPV4, and phospholipase-Cβ3 in human airway epithelia and their DEP-enhanced protein–protein complex formation. We also found that the chronic obstructive pulmonary disease (COPD)–predisposing TRPV4P19S variant enhances Ca2+ influx and MMP 1 activation, providing mechanistic linkage between man-made air pollution and human airway disease. DEP evoked protracted Ca2+ influx via TRPV4, enhanced by the COPD-predisposing human genetic polymorphism TRPV4P19S. This mechanism reprograms maladaptive inflammatory and extracellular-matrix–remodeling responses in human airways. The novel concept of air pollution–responsive ciliary signal transduction from PAR-2 to TRPV4 in human respiratory epithelia will accelerate rationally targeted therapies, possibly via the inhalatory route.
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影响因子：
--
作者：
Phan, Mimi N.;Leddy, Holly A.;Votta, Bartholomew J.;Kumar, Sanjay;Levy, Dana S.;Lipshutz, David B.;Lee, Suk Hee;Liedtke, Wolfgang;Guilak, Farshid
通讯作者：
Guilak, Farshid
影响因子：
4.8
作者：
Conant, K;St Hillaire, C;Nath, A
通讯作者：
Nath, A
影响因子：
5.5
作者：
Amadesi, Silvia;Cottrell, Graeme S.;Bunnett, Nigel W.
通讯作者：
Bunnett, Nigel W.
DOI：
10.1073/pnas.0803970105
发表时间：
2008-08-26
影响因子：
11.1
作者：
Lorenzo, Ivan M.;Liedtke, Wolfgang;Valverde, Miguel A.
通讯作者：
Valverde, Miguel A.
DOI：
10.1513/pats.200707-100rp
发表时间：
2008-07-15
期刊：
Proceedings of the American Thoracic Society
影响因子：
--
作者：
Torres-Duque, Carlos;Maldonado, Dario;Viegi, Giovanni
通讯作者：
Viegi, Giovanni