Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene.
Transient receptor potential (TRP) channels as a therapeutic target for intervention of respiratory effects and lethality from phosgene.
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DOI：
10.1016/j.toxlet.2015.11.004
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发表时间：
2016-02-26
影响因子：
3.5
通讯作者：
Ray R
中科院分区：
文献类型：
--
作者：
Andres D;Keyser B;Benton B;Melber A;Olivera D;Holmes W;Paradiso D;Anderson D;Ray R
光气(CG)是一种有毒的吸入气体和工业危害，会引起支气管收缩、血管收缩和相关的病理效应，可能危及生命。瞬时受体电位(TRP)家族的离子通道被认为是呼吸道中的特异性化学感觉分子，在暴露于各种有毒吸入危害(TIH)时，在检测、控制适应性反应和启动有害信号级联反应中发挥作用；由于TIH暴露而激活的离子通道可能导致支气管和血管收缩。采用气液界面暴露系统，研究了CG(16ppm，8min)对培养的人支气管平滑肌细胞(BSMC)和人肺微血管内皮细胞(HPMEC)内游离钙离子浓度([Ca~(2+)]i)的调节作用。两种Trp通道阻断剂SKF-96365和RR均可阻断CG引起的细胞内[Ca~(2+)]i升高。这些效应与这些化合物对小鼠全身吸入CG(8-10ppm×20分钟)造成的肺损伤和24小时死亡的体内保护作用有关。因此，Trp通道机制似乎是干预CG毒性的潜在靶点。
Phosgene (CG), a toxic inhalation and industrial hazard, causes bronchoconstriction, vasoconstriction and associated pathological effects that could be life threatening. Ion channels of the transient receptor potential (TRP) family have been identified to act as specific chemosensory molecules in the respiratory tract in the detection, control of adaptive responses and initiation of detrimental signaling cascades upon exposure to various toxic inhalation hazards (TIH); their activation due to TIH exposure may result in broncho- and vasoconstriction. We studied changes in the regulation of intracellular free Ca2+ concentration ([Ca2+]i) in cultures of human bronchial smooth muscle cells (BSMC) and human pulmonary microvascular endothelial cells (HPMEC) exposed to CG (16 ppm, 8 min), using an air/liquid interface exposure system. CG increased [Ca2+]i (p<0.05) in both cell types, The CG-induced [Ca2+]i was blocked (p<0.05) by two types of TRP channel blockers, SKF-96365, a general TRP channel blocker, and RR, a general TRPV (vanilloid type) blocker, in both BSMC and HPMEC. These effects correlate with the in vivo efficacies of these compounds to protect against lung injury and 24 hr lethality from whole body CG inhalation exposure in mice (8-10 ppm × 20 min). Thus the TRP channel mechanism appears to be a potential target for intervention in CG toxicity.