N-乙酰半胱氨酸通过调控EGFR/MAPK信号通路对慢性阻塞性肺疾病气道黏液高分泌的作用研究

doi:10.12092/j.issn.1009-2501.2019.10.006

中国临床药理学与治疗学 ›› 2019, Vol. 24 ›› Issue (10): 1120-1127.doi: 10.12092/j.issn.1009-2501.2019.10.006

N-乙酰半胱氨酸通过调控EGFR/MAPK信号通路对慢性阻塞性肺疾病气道黏液高分泌的作用研究

白学敏¹，邹立考²，金珍木³，姜利佳⁴

¹温州市中心医院药剂科，温州 325000，浙江；²浙江省军区温州离职干部休养所门诊部，温州 325000，浙江；³温州市中心医院风湿科，温州 325000，浙江；⁴温州市中心医院消化内科，温州 325000，浙江

收稿日期:2019-07-01 修回日期:2019-09-21 出版日期:2019-10-26 发布日期:2019-10-28
通讯作者: 邹立考，男，本科，副主任医师，研究方向：老年医学。 E-mail: xmb1107@163.com
作者简介:白学敏，女，本科，副主任药师，研究方向：临床药学。 Tel:13858725526 E-mail:djpfhh@163.com
基金资助:
浙江省医药卫生科技计划项目（2013KYB251）

Effects of N-acetylcysteine on regulation of EGFR/MAPK signaling pathway in airway mucus hypersecretion in chronic obstructive pulmonary disease

BAI Xuemin ¹, ZOU Likao², JIN Zhenmu³, JIANG Lijia ⁴

¹Department of Pharmacy, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China; ²Outpatient Department of Wenzhou Departing Cadre Restoration, Zhejiang Military Region, Wenzhou 325000, Zhejiang, China; ³ Department of Rheumatology, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China；⁴ Department of Gastroenterology, Wenzhou Central Hospital, Wenzhou 325000, Zhejiang, China

Received:2019-07-01 Revised:2019-09-21 Online:2019-10-26 Published:2019-10-28

摘要/Abstract

摘要：

目的:研究N-乙酰半胱氨酸（NAC）通过调控表皮生长因子受体/丝裂原活化蛋白激酶（EGFR/MAPK）信号通路对慢性阻塞性肺疾病（COPD）气道黏液高分泌的作用。方法:30只雄性清洁级Wistar大鼠，随机分为3组，各10只，对照组为健康大鼠，模型组为COPD气道黏液高分泌大鼠，NAC组自造模起予以3 mmol/kg 100 μL NAC，共30 d，比较各组肺组织病理结果、气道阻力（RL）和动态顺应性（Cdyn）、血气分析［动脉血二氧化碳分压（PaCO2）、动脉血氧分压（PaO2）］、黏膜层厚度/支气管壁厚度（Reid指数）、气道上皮阳性杯状细胞/总上皮细胞数、EGFR/MAPK信号通路蛋白［EGFR、磷酸化应激活化蛋白激酶（p-JNK）/总JNK、磷酸化-丝裂原活化蛋白激酶p38（p-P38MAPK）/总P38、磷酸化细胞外调节蛋白激酶（p-ERK）/总ERK、黏蛋白5AC（MUC5AC）］表达。结果:对照组上皮细胞、气道黏膜上皮、黏膜下腺体、支气管管壁无异常，管腔无分泌物；模型组肺间质血管充血，肺泡间隔变薄、断裂，相邻肺泡融合形成较多囊腔，上皮细胞存在明显增厚、增生、坏死脱落，黏膜下腺体肥大，杯状细胞增生，支气管周围炎性细胞浸润明显，管壁平滑肌束萎缩、断裂；NAC组与对照组相比，存在异常，但与模型组相比，各病理特征均减轻；模型组Cdyn、PaO2低于对照组，RL、PaCO2高于对照组（P＜0.05）；NAC组Cdyn、PaO2高于模型组，RL、PaCO2低于模型组（P＜0.05）；模型组Reid指数、阳性杯状细胞/总上皮细胞数高于对照组（P＜0.05）；NAC组Reid指数、阳性杯状细胞/总上皮细胞数低于模型组，但与对照组相比，差异仍具有统计学意义（P＜0.05）；模型组p-JNK/JNK、p-P38/P38、p-ERK/ERK、MUC5AC高于对照组（P＜0.05）；NAC组p-JNK/JNK、p-P38/P38、p-ERK/ERK、MUC5AC低于模型组，但与对照组相比，差异仍具有统计学意义（P＜0.05）。结论:N-乙酰半胱氨酸能通过抑制EGFR/MAPK信号通路表达，改善慢性阻塞性肺疾病支气管黏液腺体增生、杯状细胞广泛化生，抑制气道黏液高分泌状态，提高大鼠肺功能。

关键词: EGFR/MAPK信号通路, N-乙酰半胱氨酸, 慢性阻塞性肺疾病, 气道黏液, 高分泌

Abstract:

AIM: To investigate the role of N-acetylcysteine (NAC) in the regulation of epidermal growth factor receptor/mitogen-activated protein kinase (EGFR/MAPK) signaling pathway in airway mucus hypersecretion in chronic obstructive pulmonary disease (COPD) effect. METHODS: Thirty male clean Wistar rats were randomly divided into 3 groups, 10 in each group. The control group was healthy rats. The model group was COPD airway mucus hypersecretion rats. The NAC group was given 3 mmol/ from the modeling. NAC group received 3 mmol/kg 100 μL NAC for 30 days. The pathological results of lung tissue, airway resistance (RL) and dynamic compliance (Cdyn), blood gas results［arterial blood carbon dioxide partial pressure (PaCO2), arterial oxygen partial pressure (PaO2)］, mucosal thickness / bronchial wall thickness (Reid index), airway epithelial positive goblet cells / total epithelial cell number, EGFR/MAPK signaling pathway protein［EGFR, phosphorylation stress activated protein kinase (p-JNK) /Total JNK, phosphorylation-mitogen-activated protein kinase p38 (p-P38MAPK)/total P38, phosphorylated extracellular regulated protein kinase (p-ERK)/total ERK, mucin 5AC (MUC5AC)］ expression were observed and compared.RESULTS:There were no abnormalities in the epithelial cells, airway mucosa epithelium, submucosal glands, and bronchial wall of the control group. There was no secretion in the lumen. The model group showed pulmonary interstitial vascular congestion, thinning and rupture of the alveolar space, and the formation of adjacent alveolar fusion. Polycystic cavity, epithelial cells have obvious thickening, hyperplasia, necrosis, submucosal gland hypertrophy, goblet cell hyperplasia, inflammatory cell infiltration around the bronchi, atrophy and rupture of smooth muscle bundle; compared with control group tube in NAC showed no abnormalities, but compared with the model group, the pathological features were alleviated; Cdyn and PaO2 in the model group were lower than those in the control group, RL and PaCO2 were higher than those in the control group (P＜0.05); Cdyn and PaO2 in the NAC group were higher than those in the model group. RL and PaCO2 were lower than those in the model group (P＜0.05); the Reid index, positive goblet cells/total epithelial cells in the model group were higher than those in the control group (P＜0.05); Reid index, positive goblet cells/total epithelial cells in the NAC group were lower than those in the model group, but the difference was statistically significant compared with those in the control group (P＜0.05). p-JNK/JNK, p-P38/P38, p-ERK/ERK, MUC5AC of the model group were higher than those in the control group. (P＜0.05); p-JNK/JNK, p-P38/P38 p-ERK / ERK, MUC5AC of NAC group were lower than those in the model group as compared with the control group(P＜0.05). CONCLUSION: N-acetylcysteine can inhibit the expression of EGFR/MAPK signaling pathway, improve bronchial mucosal gland hyperplasia, goblet cell hyperplasia, inhibit airway mucus hypersecretion and improve rat lung features.

Key words: EGFR/MAPK signaling pathway, N-acetylcysteine, chronic obstructive pulmonary disease, airway mucus, high secretion

中图分类号:

R965.2
R56

白学敏，邹立考，金珍木，姜利佳. N-乙酰半胱氨酸通过调控EGFR/MAPK信号通路对慢性阻塞性肺疾病气道黏液高分泌的作用研究[J]. 中国临床药理学与治疗学, 2019, 24(10): 1120-1127.

BAI Xuemin, ZOU Likao, JIN Zhenmu, JIANG Lijia. Effects of N-acetylcysteine on regulation of EGFR/MAPK signaling pathway in airway mucus hypersecretion in chronic obstructive pulmonary disease[J]. Chinese Journal of Clinical Pharmacology and Therapeutics, 2019, 24(10): 1120-1127.

参考文献

［1］Blumenthal JA,Smith PJ,Durheim M,et al.Biobehavioral prognostic factors in chronic obstructive pulmonary disease:results from the inspire-II trial［J］.Psychosom Med,2016,78(2):153-162.
［2］Negewo NA, Gibson PG, McDonald VM.COPD and its comorbidities: Impact, measurement and mechanisms［J］.Respirology,2015,20(8):1160-1171.
［3］Jiang J,Wang Y,Tang X,et al.Regulation of vral infection-induced airway remodeling cytokine production by the tlr3-egfr signaling pathway in human bronchial epithelial cells［J］.COPD,2016,13(6):750-755.
［4］张吴越,顾永春,汤颖,等.甘草酸对支气管哮喘小鼠ERK1/2和p38MAPK信号通路的影响［J］.中华医学杂志,2018,98(16):1273-1278.
［5］张宇,张小辉,卢富明.吸入乙酰半胱氨酸治疗COPD的疗效及对痰液粘稠度、气道阻力的影响［J］.解放军预防医学杂志,2018,36(9):43-46.
［6］陈英,冯淬灵,李根茂,等.解毒清肺合剂对慢性阻塞性肺疾病气道黏液高分泌模型大鼠Egfr/mapk信号转导通路的影响［J］.中华中医药杂志,2016,31(5):1996-2001.
［7］Pavasini R,Tavazzi G,Biscaglia S,et al.Amino terminal pro brain natriuretic peptide predicts all-cause mortality in patients with chronic obstructive pulmonary disease: Systematic review and meta-analysis［J］.Chron Respir Dis,2017,14(2):117-126.
［8］Müllerova H,Maselli DJ,Locantore N,et al.Hospitalized exacerbations of COPD: risk factors and outcomes in the ECLIPSE cohort［J］.Chest,2015,147(4):999-1007.
［9］Lee JW, Park JW, Kwon OK, et al.NPS2143 Inhibits MUC5AC and proinflammatory mediators in cigarette smoke extract (CSE)-stimulated human airway epithelial cells［J］.Inflammation,2017,40(1):184-194.
［10］Zhou JS, Zhao Y, Zhou HB, et al. Autophagy plays an essential role in cigarette smoke-induced expression of MUC5AC in airway epithelium［J］.Am J Physiol Lung Cell Mol Physiol,2016,310(11):L1042-L1052.
［11］Li Q, Li N, Liu CY, et al. Ezrin/Exocyst complex regulates mucin 5AC secretion induced by neutrophil elastase in human airway epithelial cells［J］.Cell Physiol Biochem,2015,35(1):326-338.
［12］Kwak S, Kim YD, Na HG, et al. Resistin upregulates MUC5AC/B mucin gene expression in human airway epithelial cells［J］.Biochem Biophys Res Commun,2018,499(3):655-661.
［13］Na HG, Bae CH, Choi YS, et al. Spleen tyrosine kinase induces MUC5AC expression in human airway epithelial cell［J］.Am J Rhinol Allergy,2016,30(2):89-93.
［14］Currier MG, Lee S, Stobart CC, et al. EGFR interacts with the fusion protein of respiratory syncytial virus strain 2-20 and mediates infection and mucin expression［J］.PLoS Pathog,2016,12(5):e1005622.
［15］Takezawa K, Ogawa T, Shimizu S, et al. Epidermal growth factor receptor inhibitor AG1478 inhibits mucus hypersecretion in airway epithelium［J］.Am J Rhinol Allergy,2016,30(1):1-6.
［16］Kanai K, Koarai A, Shishikura Y, et al. Cigarette smoke augments MUC5AC production via the TLR3-EGFR pathway in airway epithelial cells［J］.Respir Investig,2015,53(4):137-148.
［17］Kang JH, Hwang SM, Chung IY.S100A8, S100A9 and S100A12 activate airway epithelial cells to produce MUC5AC via extracellular signal-regulated kinase and nuclear factor-κB pathways［J］.Immunol,2015,144(1):79-90.
［18］Limvuttegrijerat T, Poachanukoon O, Koontongkaew S, et al. Crude ethanolic extracts of Zingiber cassumunar ROXB. inhibit PMA-induced MUC2 and MUC5AC expression via ERK inhibition in human airway epithelial cells［J］.Asian Pac J Allergy Immunol,2014,32(4):328-336.
［19］Xu Q, Chen LX, Ran DH, et al. Bombesin receptor-activated protein regulates neutrophil elastase-induced mucin5AC hypersecretion in human bronchial epithelial cells［J］.Exp Cell Res,2017,357(2):145-154.
［20］Du W, Su J, Ye D, et al. Pinellia ternata attenuates mucus secretion and airway inflammation after inhaled corticosteroid withdrawal in copd rats［J］.Am J Chin Med,2016,44(5):1027-1041.
［21］陈英,冯淬灵,李根茂,等.清金化痰汤对慢性阻塞性肺疾病气道黏液高分泌模型大鼠表皮生长因子受体/MAPK 信号通路的影响［J］.中国中医药信息杂志,2016,23(10):56-62.
［22］Bae CH, Choi YS, Na HG, et al. Interleukin (IL) 36 gamma induces mucin 5AC, oligomeric mucus/gel-forming expression via IL-36 receptor-extracellular signal regulated kinase 1 and 2, and p38-nuclear factor kappa-light-chain-enhancer of activated B cells in human airway epithelial cells［J］.Am J Rhinol Allergy,2018,32(2):87-93.
［23］Lee EJ, Song KJ, Hwang HJ, et al. Effectiveness of atorvastatin in suppressing MUC5AC gene expression in human airway epithelial cells［J］.Int Forum Allergy Rhinol,2016,6(11):1159-1166.
［24］Lee JW, Kim YI, Im CN, et al. Grape seed proanthocyanidin inhibits mucin synthesis and viral replication by suppression of ap-1 and nf-kb via p38 mapks/jnk signaling pathways in respiratory syncytial virus-infected a549 cells［J］.J Agric Food Chem,2017,65(22):4472-4483.

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N-乙酰半胱氨酸通过调控EGFR/MAPK信号通路对慢性阻塞性肺疾病气道黏液高分泌的作用研究

Effects of N-acetylcysteine on regulation of EGFR/MAPK signaling pathway in airway mucus hypersecretion in chronic obstructive pulmonary disease

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