Wang Rong, Xiao Xue, Shen Zhenxing, Cao Lei, Cao Yongxiao
Department of Pharmacology, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi, China.
Department of Pharmacy, the Second Affiliated Hospital of Xi'an Medical University, Xi'an, Shaanxi, China.
Environ Toxicol. 2017 Feb;32(2):371-381. doi: 10.1002/tox.22241. Epub 2016 Feb 24.
Regarding the human health effects, airborne fine particulate matter 2.5 (PM ) is an important environmental risk factor. However, the underlying molecular mechanisms are largely unknown. The present study examined the hypothesis that PM causes bronchial hyperreactivity by upregulated muscarinic receptors via the mitogen-activated protein kinase (MAPK) pathway. The isolated rat bronchi segments were cultured with different concentration of PM for different time. The contractile response of the bronchi segments were recorded by a sensitive myograph. The mRNA and protein expression levels of M muscarinic receptors were studied by quantitative real-time PCR and immunohistochemistry, respectively. The muscarinic receptors agonist, carbachol induced a remarkable contractile response on fresh and DMSO cultured bronchial segments. Compared with the fresh or DMSO culture groups, 1.0 µg/mL of PM cultured for 24 h significantly enhanced muscarinic receptor-mediated contractile responses in bronchi with a markedly increased maximal contraction. In addition, the expression levels of mRNA and protein for M muscarinic receptors in bronchi of PM group were higher than that of fresh or DMSO culture groups. SB203580 (p38 inhibitor) and U0126 (MEK1/2 inhibitor) significantly inhibited the PM -induced enhanced contraction and increased mRNA and protein expression of muscarinic receptors. However, JNK inhibitor SP600125 had no effect on PM -induced muscarinic receptor upregulation and bronchial hyperreactivity. In conclusion, airborne PM upregulates muscarinic receptors, which causes subsequently bronchial hyperreactivity shown as enhanced contractility in bronchi. This process may be mediated by p38 and MEK1/2 MAPK pathways. © 2016 Wiley Periodicals, Inc. Environ Toxicol 32: 371-381, 2017.
关于对人类健康的影响，空气中的细颗粒物2.5（PM ）是一个重要的环境风险因素。然而，其潜在的分子机制在很大程度上尚不清楚。本研究检验了一个假设，即PM通过有丝分裂原活化蛋白激酶（MAPK）途径上调毒蕈碱受体，从而导致支气管高反应性。将分离的大鼠支气管段用不同浓度的PM培养不同时间。通过灵敏的肌动描记器记录支气管段的收缩反应。分别通过定量实时PCR和免疫组织化学研究M毒蕈碱受体的mRNA和蛋白表达水平。毒蕈碱受体激动剂卡巴胆碱对新鲜培养和二甲基亚砜（DMSO）培养的支气管段均诱导出显著的收缩反应。与新鲜培养组或DMSO培养组相比，1.0μg/mL的PM培养24小时显著增强了支气管中毒蕈碱受体介导的收缩反应，最大收缩明显增加。此外，PM组支气管中M毒蕈碱受体的mRNA和蛋白表达水平高于新鲜培养组或DMSO培养组。SB203580（p38抑制剂）和U0126（MEK-1/2抑制剂）显著抑制了PM诱导的收缩增强以及毒蕈碱受体mRNA和蛋白表达的增加。然而，JNK抑制剂SP600125对PM诱导的毒蕈碱受体上调和支气管高反应性没有影响。总之，空气中的PM上调毒蕈碱受体，随后导致支气管高反应性，表现为支气管收缩性增强。这个过程可能由p38和MEK-1/2 MAPK途径介导。©2016威利期刊公司。《环境毒理学》32: 371 - 381，2017年。
