上海交通大学学报（医学版）

上海交通大学学报（医学版） >

2022 , Vol. 42 >Issue 5: 667 - 672

DOI: https://doi.org/10.3969/j.issn.1674-8115.2022.05.016

综述

褪黑素在哮喘发病和病程中的作用机制研究进展

  • 康文慧 ,
  • 陈仪婷 ,
  • 赵安达 ,
  • 李荣 ,
  • 李生慧
展开
  • 1.上海交通大学公共卫生学院，上海 200025
    2.上海交通大学医学院附属第九人民医院营养科，上海 200011
康文慧（1997—），女，硕士生；电子信箱：18717805230@163.com。
李生慧，电子信箱：lsh9907@163.com。

收稿日期: 2022-02-22

  录用日期: 2022-05-22

  网络出版日期: 2022-05-28

基金资助

国家自然科学基金(81874266)

收起

Research progress of the mechanism of melatonin in the pathogenesis and course of asthma

  • Wenhui KANG ,
  • Yiting CHEN ,
  • Anda ZHAO ,
  • Rong LI ,
  • Shenghui LI
Expand
  • 1.School of Public Health, Shanghai Jiao Tong University, Shanghai 200025, China
    2.Department of Nutrition, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200011, China
LI Shenghui, E-mail: lsh9907@163.com.

Received date: 2022-02-22

  Accepted date: 2022-05-22

  Online published: 2022-05-28

Supported by

National Natural Science Foundation of China(81874266)

Fold

摘要

褪黑素（melatonin）是由松果体分泌的激素之一，其调控昼夜节律和改善睡眠的功效已被广泛研究和证实。已有研究认为褪黑素过量或分泌紊乱能导致不良的健康效应。近年来，不断积累的证据显示褪黑素在抗炎、抗癌、免疫调节等方面发挥重要作用。加之褪黑素不仅可以在人体合成，且易于通过外源性途径获取，因此，其对人体健康的影响备受关注。该文以褪黑素参与气道炎症和气道重塑调控为切入点，系统检索、筛选了截至2022年2月的相关文献37篇，分析了褪黑素对哮喘的影响及相关机制。结果显示，褪黑素一方面可以通过抑制磷酸化信号通路影响基因转录、翻译，阻断核因子κB（nuclear factor-κB，NF-κB）的激活，进而改变呼吸道细胞因子和炎症细胞的表达，减少嗜酸性粒细胞等炎症细胞的生成和募集，抑制白细胞介素-1β（interleukin-1β，IL-1β）、IL-4、IL-6、胱天蛋白酶-1（caspase-1）等细胞因子和酶，减少黏液的产生，发挥抑制气道炎症的作用，并可以拮抗哮喘的外源性加重和特应性进程。另一方面，褪黑素能够通过作用于基质金属蛋白酶9（matrix metalloproteinase-9，MMP-9），减少胶原沉积，抑制杯状细胞增生，改善平滑肌细胞表型而实现抑制气道重塑。上述结论均提示褪黑素具有通过气道炎症和气道重塑调控哮喘发病进程的潜力，围绕褪黑素的免疫调节功能开展深入探索有望为哮喘防治提供新思路。

关键词： 褪黑素; 哮喘; 气道炎症; 气道重塑

本文引用格式

康文慧 , 陈仪婷 , 赵安达 , 李荣 , 李生慧 . 褪黑素在哮喘发病和病程中的作用机制研究进展[J]. 上海交通大学学报（医学版）, 2022 , 42(5) : 667 -672 . DOI: 10.3969/j.issn.1674-8115.2022.05.016

Abstract

Melatonin is one of the hormones secreted by the pineal gland. The efficacy of melatonin in regulating circadian rhythm and improving sleep has been widely explored and confirmed. Studies have shown that excessive secretion or disordered melatonin can lead to adverse health effects. In recent years, accumulated evidence shows that melatonin plays an important role in anti-inflammatory, anti-cancer, immune regulation, and so on. In addition, melatonin can not only be synthesized in the human body, but also be easily obtained through external sources. Therefore, its impact on human body has attracted much attention. Based on the involvement of melatonin in airway inflammation and airway remodeling, this study systematically searched and screened 37 relevant literatures up to February 2022 and analyzed the effect of melatonin on asthma and its related mechanisms. The results showed that, on one hand, melatonin could affect gene transcription and translation by inhibiting phosphorylation signaling pathway and blocking the activation of nuclear factor-κB (NF-κB), thereby changing the expression of respiratory cytokines and inflammatory cells, reducing the generation and recruitment of eosinophils and other inflammatory cells, inhibiting cytokines and enzymes such as interleukin-1β (IL-1β), IL-4, IL-6 and caspase-1, reducing the production of mucus, playing a role in inhibiting airway inflammation, and also antagonizing the exogenous exacerbation and atopic process of asthma. On the other hand, melatonin can inhibit airway remodeling by acting on matrix metalloproteinase-9 (MMP-9), reducing collagen deposition, inhibiting goblet cell proliferation and improving smooth muscle cell phenotype. All these findings suggest that melatonin has the potential to regulate the pathogenesis of asthma by inhibiting airway inflammation and remodeling. Further exploration on the immunomodulatory function of melatonin is expected to provide new ideas for the prevention and treatment of asthma.

Key words： melatonin; asthma; airway inflammation; airway remodeling

参考文献

1 GBD 2015 Chronic Respiratory Disease Collaborators. Global, regional, and national deaths, prevalence, disability-adjusted life years, and years lived with disability for chronic obstructive pulmonary disease and asthma, 1990—2015: a systematic analysis for the Global Burden of Disease Study 2015[J]. Lancet Respir Med, 2017, 5(9): 691-706.
2 刘传合, 洪建国, 尚云晓, 等. 中国16城市儿童哮喘患病率20年对比研究[J]. 中国实用儿科杂志, 2015, 30(8): 596-600.
2 LIU C H, HONG J G, SHANG Y X, et al. Comparison of asthma prevalence in children from 16 cities of China in 20 years[J]. Chin J Pract Pediatr, 2015, 30(8): 596-600.
3 HUANG K, YANG T, XU J, et al. Prevalence, risk factors, and management of asthma in China: a national cross-sectional study[J]. Lancet, 2019, 394(10196): 407-418.
4 PAPI A, BRIGHTLING C, PEDERSEN S E, et al. Asthma[J]. Lancet, 2018, 391(10122): 783-800.
5 WITHYACHUMNARNKUL B, NONAKA K O, Santana C, et al. Interferon-gamma modulates melatonin production in rat pineal glands in organ culture[J]. J Interferon Res, 1990, 10(4): 403-411.
6 BHATTACHARYA S, PATEL K K, DEHARI D, et al. Melatonin and its ubiquitous anticancer effects[J]. Mol Cell Biochem, 2019, 462(1/2): 133-155.
7 赵燕, 王东华, 赵曦阳. 植物中褪黑素的研究进展[J]. 西北植物学报, 2014, 34(01): 196-205.
7 ZHAO Y, WANG D, ZHAO X. Recent advance on the melatonin in plant[J]. Acta Bot Boreal Occident Sin, 2014, 34(01): 196-205.
8 REITER R J. Pineal melatonin: cell biology of its synthesis and of its physiological interactions[J]. Endocr Rev, 1991, 12(2): 151-180.
9 CLAUSTRAT B, LESTON J. Melatonin: physiological effects in humans[J]. Neurochirurgie, 2015, 61(2/3): 77-84.
10 MAZZOCCOLI G, KVETNOY I, MIRONOVA E, et al. The melatonergic pathway and its interactions in modulating respiratory system disorders[J]. Biomed Pharmacother, 2021, 137: 111397.
11 费广鹤, 刘荣玉, 周江宁. 唾液中游离皮质醇和松果体素水平昼夜节律性变化与夜间哮喘相关性研究[J]. 中国药理学通报, 2002, 18(6): 685-688.
11 FEI G H, LIU R Y, ZHOU J N. Alterations in chronobiology of salivary cortisol and melatonin in nocturnal asthma[J]. Chin Pharmacol Bull, 2002, 18(6): 685-688.
12 费广鹤, 刘荣玉, 张志红, 等. 支气管哮喘患者唾液褪黑素和皮质醇水平及其与病情的关系[J]. 中华结核和呼吸杂志, 2003, (11): 26-29.
12 FEI G H, LIU R Y, ZHANG Z H, et al. Relationships between melatonin and cortisol and the status of disease in patients with bronchial asthma[J]. Chin J Tuberc Respir Dis, 2003, (11): 26-29.
13 FEI G H, LIU R Y, ZHANG Z H, et al. Alterations in circadian rhythms of melatonin and cortisol in patients with bronchial asthma[J]. Acta Pharmacol Sin, 2004, 25(5): 651-656.
14 GUMRAL N, CALISKAN S, OZGüNER F, et al. Melatonin levels and enzymatic antioxidant defense system decrease in blood of patients with bronchial asthma[J]. Toxicol Ind Heal, 2009, 25(6): 411-416.
15 GUMRAL N, NAZIROGLU M, ONGEL K, et al. Antioxidant enzymes and melatonin levels in patients with bronchial asthma and chronic obstructive pulmonary disease during stable and exacerbation periods[J]. Cell Biochem Funct, 2009, 27(5): 276-283.
16 LITVINENKO G I, SHURLYGINA A V, SHIRINSKII V S, et al. Circadian variations in immune values and serum melatonin in asthmatics[J]. Bull Exp Biol Med, 2006, 142(5): 605-608.
17 EVSYUKOVA H V. Expression of melatonin in platelets of patients with aspirin-induced asthma[J]. Eur J Clin Investig, 2011, 41(7): 781-784.
18 王敏, 谢利波, 张光环, 等. 支气管哮喘患儿血清褪黑素水平检测的意义[J]. 实用儿科临床杂志, 2007, 22(4): 269-270.
18 WANG M, XIE L B, ZHANG G H, et al. Changes of melatonin in asthmatic children and its significance[J]. J Appl Clin Pediatr, 2007, 22(4): 269-270.
19 陈雯, 费广鹤. 哮喘大鼠血清褪黑素及海马褪黑素受体1的变化[J]. 中国药理学通报, 2014, 30(8): 1142-1146.
19 CHEN W, FEI G H. Serum melatonin and hippocampus MT1 overexpression in asthmatic rat models[J]. Chin Pharmacol Bull, 2014, 30(8): 1142-1146.
20 SUTHERLAND E R, ELLISON M C, KRAFT M, et al. Elevated serum melatonin is associated with the nocturnal worsening of asthma[J]. J Allergy Clin Immunol, 2003, 112(3): 513-517.
21 王亚亭, 陈胜利, 徐叔云. 褪黑素对哮喘大鼠核因子-κB表达的影响及抗炎作用[J]. 中华儿科杂志, 2004, 42(02): 94-97, C2-1.
21 WANG Y T, CHEN S L, XU S Y. Effect of melatonin on the expression of nuclear factor-κB and airway inflammation in asthmatic rats[J]. Chin J Pediatr, 2004, 42(02): 94-97, C2-1.
22 王友刚, 郑子龙, 韩曼, 等. 褪黑素对邻苯二甲酸二丁酯加重小鼠过敏性哮喘的拮抗作用[J]. 环境与健康杂志, 2020, 37(1): 6-10, 封2.
22 WANG Y G, ZHEN Z L, HAN M, et al. Antagonistic effects of melatonin on dibutyl phthalate-aggravated allergic asthma[J]. J Environ Health, 2020, 37(1): 6-10, cover 2.
23 SHIN I S, PARK J W, SHIN N R, et al. Melatonin reduces airway inflammation in ovalbumin-induced asthma[J]. Immunobiology, 2014, 219(12): 901-908.
24 姚钧兰, 王敏, 张光环, 等. 褪黑激素对哮喘大鼠的防治作用[J]. 中国新药与临床杂志, 2009, 28(2): 147-150.
24 YAO J L, WANG M, ZHANG G H, et al. Therapeutic and preventive effects of melatonin on asthmathic rats[J]. Chin J New Drugs Clin Rem, 2009, 28(2): 147-150.
25 LU T, GALIJASEVIC S, ABDULHAMID I, et al. Analysis of the mechanism by which melatonin inhibits human eosinophil peroxidase[J]. Br J Pharmacol, 2008, 154(6): 1308-1317.
26 CHEN C F, WANG D, REITER R J, et al. Oral melatonin attenuates lung inflammation and airway hyperreactivity induced by inhalation of aerosolized pancreatic fluid in rats[J]. J Pineal Res, 2011, 50(1): 46-53.
27 WU H M, XIE Q M, ZHAO C C, et al. Melatonin biosynthesis restored by CpG oligodeoxynucleotides attenuates allergic airway inflammation via regulating NLRP3 inflammasome[J]. Life Sci, 2019, 239: 117067.
28 王敏, 李美容, 张光环, 等. 褪黑素促进哮喘小鼠肺组织STAT4的表达及抑制气道炎症[J]. 基础医学与临床, 2011, 31(2): 179-182.
28 WANG M, LI M R, ZHANG G H, et al. Oral melatonin attenuates lung inflammation and airway hyperreactivity induced by inhalation of aerosolized pancreatic fluid in rats[J]. Basic ＆ Clinical Medicine, 2011, 31(2): 179-182.
29 KIM G D, LEE S E, KIM T H, et al. Melatonin suppresses acrolein-induced IL-8 production in human pulmonary fibroblasts[J]. J Pineal Res, 2012, 52(3): 356-364.
30 SHIN I S, PARK J W, SHIN N R, et al. Melatonin inhibits MUC5AC production via suppression of MAPK signaling in human airway epithelial cells[J]. J Pineal Res, 2014, 56(4): 398-407.
31 ZHOU S Y, HAN M, REN Y L, et al. Dibutyl phthalate aggravated asthma-like symptoms through oxidative stress and increasing calcitonin gene-related peptide release[J]. Ecotoxicol Environ Saf, 2020, 199: 110740.
32 LIU X, ZHANG Y, REN Y, et al. Melatonin prevents allergic airway inflammation in epicutaneously sensitized mice[J]. Biosci Rep, 2021, 41(9): BSR20210398. DOI: 10.1042/BSR20210398.
33 黄绍光, 康健, 林江涛, 等. 慢性气道炎症性疾病气道黏液高分泌管理中国专家共识[J].中华结核和呼吸杂志, 2015, 38(10): 723-729.
33 HUANG S G, KANG J, LIN J T, et al. Chinese expert consensus on the management of airway mucus hypersecretion in chronic airway inflammatory diseases[J]. Chin J Tuberc Respir Dis, 2015, 38(10): 723-729.
34 蒋红, 钟晓方, 吴玉兰, 等. 儿童哮喘与血清褪黑素及环氧化酶-2水平的相关性[J]. 中华妇幼临床医学杂志, 2009, 5(3): 32-34.
34 JIANG H, ZHONG X F, WU Y L, et al. Level of serum melatonin and cycloxooygenase-2 and its relativity in asthmatic children[J]. Chin J Obs/Gyne & Pediatr(Electronic Version), 2009, 5(3): 32-34.
35 HE L C, NORRIS C, CUI X X, et al. Role of endogenous melatonin in pathophysiologic and oxidative stress responses to personal air pollutant exposures in asthmatic children[J]. Sci Total Environ, 2021, 773: 145709.
36 CHEN Y S, WU X Y, YANG X, et al. Melatonin antagonizes ozone-exacerbated asthma by inhibiting the TRPV1 channel and stabilizing the Nrf2 pathway[J]. Environ Sci Pollut Res Int, 2021, 28(42): 59858-59867.
37 WU H M, SHEN Q Y, FANG L, et al. JNK-TLR9 signal pathway mediates allergic airway inflammation through suppressing melatonin biosynthesis[J]. J Pineal Res, 2016, 60(4): 415-423.
38 WU H M, ZHAO C C, XIE Q M, et al. TLR2-melatonin feedback loop regulates the activation of NLRP3 inflammasome in murine allergic airway inflammation[J]. Front Immunol, 2020, 11: 172.
39 SUTHERLAND E R, MARTIN R J, ELLISON M C, et al. Immunomodulatory effects of melatonin in asthma[J]. Am J Respir Crit Care Med, 2002, 166(8): 1055-1061.
40 JR MARTINS E, LIGEIRO DE OLIVEIRA A P, FIALHO DE ARAUJO A M, et al. Melatonin modulates allergic lung inflammation[J]. J Pineal Res, 2001, 31(4): 363-369.
41 LUO F, LIU X, LI S, et al. Melatonin promoted chemotaxins expression in lung epithelial cell stimulated with TNF-α[J]. Respir Res, 2004, 5(1): 20.
42 WINKLER K, MARTIN D, NOWAKOWSKI M, et al. Low Levels of melatonin increase nitric oxide production from IFN-γ/vitamin D stimulated PBMC and may contribute to seasonal increase in angiodema in summer[J]. J Allergy Clin Immunol, 2016, 137(2): AB247-AB247.
43 钱朝霞, 刘荣玉, 周丽. 褪黑素及其受体拮抗剂对哮喘小鼠模型气道炎症和气道重构的调节作用[J]. 中国呼吸与危重监护杂志, 2006, 5(2): 117-121, 162.
43 QIAN Z X, LIU R Y, ZHOU L. Effects of melatonin and its receptor antagonist luzindole on airway inflammation and remodeling in a mouse asthma model[J]. Chin J Respir Crit Care Med, 2006, 5(2): 117-121, 162.
44 王敏, 李蓓, 张光环. 褪黑素减轻哮喘小鼠结缔组织生长因子的表达和抑制气道重构[J]. 基础医学与临床, 2010, 30(3): 258-262.
44 WANG M, LI B, ZHANG G H. Melatonin decreases the expression of connective tissue growth factor and inhibite airway remodeling in asthmatic mouse[J]. Basic ＆ Clin Med, 2010, 30(3): 258-262.
45 周莉, 钱朝霞, 李锋, 等. 褪黑素对支气管哮喘小鼠胶原沉积及基质金属蛋白酶9和基质金属蛋白酶组织抑制剂1mRNA与蛋白表达的动态调节[J]. 中华结核和呼吸杂志, 2007, 30(7): 527-532.
45 ZHOU L, QIAN Z X, LI F, et al. The effect of melatonin on the regulation of collagen accumulation and matrix metalloproteinase-9 and tissue inhibitor of matrix metalloproteinase-1 mRNA and protein in a murine model of chronic asthma[J]. Chin J Tuberc Respir Dis, 2007, 30(7): 527-532.
46 YU Q J, YU X W, ZHONG X H, et al. Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma[J]. Cell Tissue Res, 2020, 380(1): 129-142.
47 WEEKLEY L B. Influence of melatonin on bovine pulmonary vascular and bronchial airway smooth muscle tone[J]. Clin Auton Res, 1995, 5(1): 53-56.
48 KARASU-MINARECI E, KAYA Y, BELGIN YILDIRIM F. The achilles heel in melatonin: asthma[J]. Iran J Allergy Asthma Immunol, 2012, 11(3): 246-252.
Options
文章导航

/

〈 〉