Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung
Role of transient receptor potential and pannexin channels in cigarette smoke-triggered ATP release in the lung
复制标题
DOI：
10.1136/thoraxjnl-2014-205467
复制
发表时间：
2014-12-01
期刊：
影响因子：
10
通讯作者：
Birrell, Mark A.
中科院分区：
文献类型：
--
作者：
Baxter, Matthew;Eltom, Suffwan;Birrell, Mark A.
COPD是一种炎症性疾病，通常与吸烟（CS）有关，全球患病率不断增加，且无有效药物治疗。细胞外ATP在COPD影响的肺中增加，并且可能在驱动CS诱导的气道炎症中起关键作用，但ATP释放的机制一直困扰着研究人员。最近，瞬时受体电位（TRP）和泛连接蛋白-1通道已被建议在其他实验范式中发挥作用。因此，这项工作的目的是调查，如果这些通道参与CS诱导的ATP释放在lung.Methods原代人类细胞暴露于CS和细胞外ATP水平测定。将小鼠暴露于主流CS并评估气道炎症。TRPV 1/4 mRNA在人肺实质中的表达进行了评估。结果CS暴露引起原代气道支气管上皮细胞ATP的剂量相关性增加。TRPV 1、TRPV 4和泛连接蛋白-1通道阻断剂可减弱这种作用。使用小鼠急性CS驱动模型系统获得平行数据。结论COPD患者肺组织中细胞外ATP含量增加，可能在COPD的病理生理过程中起重要作用。这些实验揭示了一种新的机制，这可能是负责CS诱导的ATP释放。这些发现突出了新的目标，可能导致药物的发展，以治疗这种毁灭性的疾病。
Background COPD is an inflammatory disease usually associated with cigarette smoking (CS) with an increasing global prevalence and no effective medication. Extracellular ATP is increased in the COPD affected lung and may play a key role in driving CS-induced airway inflammation, but the mechanism involved in ATP release has eluded researchers. Recently, the transient receptor potential (TRP) and pannexin-1 channels have been suggested to play a role in other experimental paradigms. Thus, the aim of this work is to investigate if these channels are involved in CS-induced ATP release in the lung.Methods Primary human cells were exposed to CS and extracellular ATP levels measured. Mice were exposed to mainstream CS and airway inflammation assessed. TRPV1/4 mRNA expression was assessed in human lung parenchyma.Results CS exposure caused a dose-related increase in ATP from primary airway bronchial epithelial cells. This was attenuated by blockers of TRPV1, TRPV4 and pannexin-1 channels. Parallel data was obtained using murine acute CS-driven model systems. Finally, TRPV1/4 mRNA expression was increased in lung tissue samples from patients with COPD.Conclusions Extracellular ATP is increased in the COPD affected lung and may play a key role in driving disease pathophysiology. These experiments uncover a novel mechanism which may be responsible for CS-induced ATP release. These findings highlight novel targets that could lead to the development of medicine to treat this devastating disease.