Skip to main content

Advertisement

SpringerLink
Log in

Melatonin antagonizes ozone-exacerbated asthma by inhibiting the TRPV1 channel and stabilizing the Nrf2 pathway

  • Research Article
  • Published:
Environmental Science and Pollution Research Aims and scope Submit manuscript

Abstract

Over the past few years, ozone has been identified as a potential risk factor for exacerbating asthma. However, few attempts have been made to prevent the progression of ozone-exacerbated asthma. This study investigated the attenuating effects of melatonin on ozone-aggravated allergic asthma, and explored the changes to the transient receptor potential vanilloid 1 (TRPV1)-nuclear factor erythroid-derived 2-related factor 2 (Nrf2) pathway associated with melatonin treatment. The levels of TRPV1 and calcitonin gene-related peptides (CGRP) in lung tissue were detected by immunohistochemistry, western blot, and enzyme-linked immunosorbent assay (ELISA). The Nrf2 signaling involved proteins and mRNA were evaluated by western blot and RT-qPCR. The change of Immunoglobulin E (IgE) and T helper (Th) 2 and Th17 cytokines in serum and bronchoalveolar lavage fluid (BALF) was determined by ELISA. Recruitment of inflammatory cells in BALF, histopathological changes, and airway hyperresponsiveness (AHR) were also determined in lung tissues. Our results indicated that melatonin treatment significantly reduced oxidative stress, as indicated by levels of glutathione (GSH), malonaldehyde (MDA), and 8-hydroxy-2-deoxyguanosine (8-OH-dG). Moreover, ozone-exacerbated asthma symptoms, such as inflammatory cell infiltration, levels of serum immunoglobulin, Th2 and Th17 cytokines in BALF, obvious changes in lung histology, and AHR, were all ameliorated by melatonin treatment. Interestingly, melatonin not only markedly decreased the protein levels of TRPV1 and CGRP, but also enhanced the expression of Nrf2, quinone oxidoreductase-1 (NQO-1), and heme oxygenase-1 (HO-1). Taken together, our results demonstrate that melatonin administration could antagonize ozone-exacerbated asthma by inhibiting the TRPV1 channel and stabilizing the Nrf2 pathway.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data availability

Not applicable.

References

  • Barnes PJ (2008) The cytokine network in asthma and chronic obstructive pulmonary disease. J Clin Invest 118:3546–3556

    Article  CAS  Google Scholar 

  • Brightling CE, Symon FA, Birring SS, Bradding P, Pavord ID, Wardlaw AJ (2002) TH2 cytokine expression in bronchoalveolar lavage fluid T lymphocytes and bronchial submucosa is a feature of asthma and eosinophilic bronchitis. J Allergy Clin Immunol 110:899–905

    Article  CAS  Google Scholar 

  • Buendia I, Tenti G, Michalska P, Méndez-López I, Luengo E, Satriani M, Padín-Nogueira F, López MG, Ramos MT, García AG, Menéndez JC, León R (2017) ITH14001, a CGP37157-nimodipine hybrid designed to regulate calcium homeostasis and oxidative stress, exerts neuroprotection in cerebral ischemia. ACS Chem Neurosci 8:67–81

    Article  CAS  Google Scholar 

  • Calvo JR, González-Yanes C, Maldonado MD (2013) The role of melatonin in the cells of the innate immunity: a review. J Pineal Res 55:103–120

    Article  CAS  Google Scholar 

  • Chen XL, Kunsch C (2004) Induction of cytoprotective genes through Nrf2/antioxidant response element pathway: a new therapeutic approach for the treatment of inflammatory diseases. Curr Pharm Des 10:879–891

    Article  CAS  Google Scholar 

  • Chen S, Deng Y, He Q, Chen Y, Wang D, Sun W, He Y, Zou Z, Liang Z, Chen R, Yao L, Tao A (2020) Toll-like receptor 4 deficiency aggravates airway hyperresponsiveness and inflammation by impairing neutrophil apoptosis in a toluene diisocyanate-induced murine asthma model. Allergy, Asthma Immunol Res 12:608–625

    Article  CAS  Google Scholar 

  • Choi JY, Lee HY, Hur J, Kim KH, Kang JY, Rhee CK, Lee SY (2018) TRPV1 blocking alleviates airway inflammation and remodeling in a chronic asthma murine model. Allergy, Asthma Immunol Res 10:216–224

    Article  CAS  Google Scholar 

  • Deering-Rice CE, Johansen ME, Roberts JK, Thomas KC, Romero EG, Lee J, Yost GS, Veranth JM, Reilly CA (2012) Transient receptor potential vanilloid-1 (TRPV1) is a mediator of lung toxicity for coal fly ash particulate material. Mol Pharmacol 81:411–419

    Article  CAS  Google Scholar 

  • Deng Y, Xu ZF, Liu W, Xu B, Yang HB, Wei YG (2012) Riluzole-triggered GSH synthesis via activation of glutamate transporters to antagonize methylmercury-induced oxidative stress in rat cerebral cortex. Oxidative Med Cell Longev 2012:534705

    Article  CAS  Google Scholar 

  • Devos FC, Boonen B, Alpizar YA, Maes T, Hox V, Seys S, Pollaris L, Liston A, Nemery B, Talavera K, Hoet PHM, Vanoirbeek JAJ (2016) Neuro-immune interactions in chemical-induced airway hyperreactivity. Eur Respir J 48:380–392

    Article  CAS  Google Scholar 

  • Dhawale VS, Amara VR, Karpe PA, Malek V, Patel D, Tikoo K (2016) Activation of angiotensin-converting enzyme 2 (ACE2) attenuates allergic airway inflammation in rat asthma model. Toxicol Appl Pharmacol 306:17–26

    Article  CAS  Google Scholar 

  • Di Q, Dai L, Wang Y, Zanobetti A, Choirat C, Schwartz JD, Dominici F (2017) Association of short-term exposure to air pollution with mortality in older adults. Jama 318:2446–2456

    Article  CAS  Google Scholar 

  • Dou T, Yan M, Wang X, Lu W, Zhao L, Lou D, Wu C, Chang X, Zhou Z (2016) Nrf2/ARE pathway involved in oxidative stress induced by paraquat in human neural progenitor cells. Oxidative Med Cell Longev 2016:8923860

    Article  CAS  Google Scholar 

  • Duan L, Li J, Ma P, Yang X, Xu S (2017) Vitamin E antagonizes ozone-induced asthma exacerbation in Balb/c mice through the Nrf2 pathway. Food Chem Toxicol 107:47–56

    Article  CAS  Google Scholar 

  • Fahy JV (2015) Type 2 inflammation in asthma--present in most, absent in many. Nat Rev Immunol 15:57–65

    Article  CAS  Google Scholar 

  • Gauthier M, Ray A, Wenzel SE (2015) Evolving concepts of asthma. Am J Respir Crit Care Med 192:660–668

    Article  CAS  Google Scholar 

  • Halim TY, Steer CA, Mathä L, Gold MJ, Martinez-Gonzalez I, McNagny KM, McKenzie AN, Takei F (2014) Group 2 innate lymphoid cells are critical for the initiation of adaptive T helper 2 cell-mediated allergic lung inflammation. Immunity 40:425–435

    Article  CAS  Google Scholar 

  • He L, Li Z, Teng Y, Cui X, Barkjohn KK, Norris C, Fang L, Lin L, Wang Q, Zhou X, Hong J, Li F, Zhang Y, Schauer JJ, Black M, Bergin MH, Zhang J(J) (2020) Associations of personal exposure to air pollutants with airway mechanics in children with asthma. Environ Int 138:105647

    Article  CAS  Google Scholar 

  • Hou X, Li H, Zhang C, Wang J, Li X, Li X (2017) Overexpression of Fibulin-5 attenuates burn-induced inflammation via TRPV1/CGRP pathway. Exp Cell Res 357:320–327

    Article  CAS  Google Scholar 

  • Huang CH, Loo EX, Kuo IC, Soh GH, Goh DL, Lee BW, Chua KY (2011) Airway inflammation and IgE production induced by dust mite allergen-specific memory/effector Th2 cell line can be effectively attenuated by IL-35. J Immunol 187:462–471

    Article  CAS  Google Scholar 

  • Huang KF, Ma KH, Hung YC, Lo LC, Lin KC, Liu PS, Hu MK, Chueh SH (2018) A new copper ionophore DPMQ protects cells against ultraviolet B irradiation by inhibiting the TRPV1 channel. J Cell Physiol 233:9594–9610

    Article  CAS  Google Scholar 

  • Huang KF, Ma KH, Chang YJ, Lo LC, Jhap TY, Su YH, Liu PS, Chueh SH (2019a) Baicalein inhibits matrix metalloproteinase 1 expression via activation of TRPV1-Ca-ERK pathway in ultraviolet B-irradiated human dermal fibroblasts. Exp Dermatol 28:568–575

    Article  CAS  Google Scholar 

  • Huang KF, Ma KH, Jhap TY, Liu PS, Chueh SH (2019b) Ultraviolet B irradiation induced Nrf2 degradation occurs via activation of TRPV1 channels in human dermal fibroblasts. Free Radic Biol Med 141:220–232

    Article  CAS  Google Scholar 

  • Jirmo AC, Busse M, Happle C, Skuljec J, Dalüge K, Habener A, Grychtol R, DeLuca DS, Breiholz OD, Prinz I, Hansen G (2020) IL-17 regulates DC migration to the peribronchial LNs and allergen presentation in experimental allergic asthma. Eur J Immunol 50:1019–1033

    Article  CAS  Google Scholar 

  • Kabata H, Artis D (2019) Neuro-immune crosstalk and allergic inflammation. J Clin Invest 130:1475–1482

    Article  Google Scholar 

  • Li, N., Alam, J., Venkatesan, M.I., Eiguren-Fernandez, A., Schmitz, D., Di Stefano, E., Slaughter, N., Killeen, E., Wang, X., Huang, A., et al. (2004). Nrf2 is a key transcription factor that regulates antioxidant defense in macrophages and epithelial cells: protecting against the proinflammatory and oxidizing effects of diesel exhaust chemicals. Journal of immunology (Baltimore, Md. : 1950) 173, 3467-3481.

  • Li YJ, Kawada T, Azuma A (2013) Nrf2 is a protective factor against oxidative stresses induced by diesel exhaust particle in allergic asthma. Oxidative Med Cell Longev 2013:323607

    Article  Google Scholar 

  • Li, J., Chen, Y., Chen, Q.Y., Liu, D., Xu, L., Cheng, G., Yang, X., Guo, Z., and Zeng, Y. (2019a). Role of transient receptor potential cation channel subfamily V member 1 (TRPV1) on ozone-exacerbated allergic asthma in mice. Environmental pollution (Barking, Essex : 1987) 247, 586-594.

  • Li M, Fan X, Ji L, Fan Y, Xu L (2019b) Exacerbating effects of trimellitic anhydride in ovalbumin-induced asthmatic mice and the gene and protein expressions of TRPA1, TRPV1, TRPV2 in lung tissue. Int Immunopharmacol 69:159–168

    Article  CAS  Google Scholar 

  • Liu Y, Pan J, Zhang H, Shi C, Li G, Peng Z, Ma J, Zhou Y, Zhang L (2019) Short-term exposure to ambient air pollution and asthma mortality. Am J Respir Crit Care Med 200:24–32

    Article  CAS  Google Scholar 

  • Mauriz JL, Collado PS, Veneroso C, Reiter RJ, González-Gallego J (2013) A review of the molecular aspects of melatonin’s anti-inflammatory actions: recent insights and new perspectives. J Pineal Res 54:1–14

    Article  CAS  Google Scholar 

  • McGarvey LP, Butler CA, Stokesberry S, Polley L, McQuaid S, Abdullah H, Ashraf S, McGahon MK, Curtis TM, Arron J et al (2014) Increased expression of bronchial epithelial transient receptor potential vanilloid 1 channels in patients with severe asthma. J Allergy Clin Immunol 133:704–712.e704

    Article  CAS  Google Scholar 

  • Mikami N, Watanabe K, Hashimoto N, Miyagi Y, Sueda K, Fukada S, Yamamoto H, Tsujikawa K (2012) Calcitonin gene-related peptide enhances experimental autoimmune encephalomyelitis by promoting Th17-cell functions. Int Immunol 24:681–691

    Article  CAS  Google Scholar 

  • Mustafa AS (2020) Vaccine potential of mycobacterial antigens against asthma. Med Princ Pract 29(5):404–411

  • Nabe T (2020) Steroid-resistant asthma and neutrophils. Biol Pharm Bull 43:31–35

    Article  CAS  Google Scholar 

  • Nagashima H, Mahlakõiv T, Shih HY, Davis FP, Meylan F, Huang Y, Harrison OJ, Yao C, Mikami Y, Urban JF Jr et al (2019) Neuropeptide CGRP limits group 2 innate lymphoid cell responses and constrains type 2 inflammation. Immunity 51:682–695.e686

    Article  CAS  Google Scholar 

  • Nakagome K, Nagata M (2018) Involvement and possible role of eosinophils in asthma exacerbation. Front Immunol 9:2220

    Article  CAS  Google Scholar 

  • Nuvolone D, Petri D, Voller F (2018) The effects of ozone on human health. Environ Sci Pollut Res Int 25:8074–8088

    Article  CAS  Google Scholar 

  • Rahman I, Biswas SK, Kode A (2006) Oxidant and antioxidant balance in the airways and airway diseases. Eur J Pharmacol 533:222–239

    Article  CAS  Google Scholar 

  • Sakurai H, Morishima Y, Ishii Y, Yoshida K, Nakajima M, Tsunoda Y, Hayashi SY, Kiwamoto T, Matsuno Y, Kawaguchi M, Yamamoto M, Hizawa N (2018) Sulforaphane ameliorates steroid insensitivity through an Nrf2-dependent pathway in cigarette smoke-exposed asthmatic mice. Free Radic Biol Med 129:473–485

    Article  CAS  Google Scholar 

  • Schatz M, Rosenwasser L (2014) The allergic asthma phenotype. J Allergy Clin Immunol Pract 2:645–648 quiz 649

    Article  Google Scholar 

  • Shin IS, Park JW, Shin NR, Jeon CM, Kwon OK, Kim JS, Kim JC, Oh SR, Ahn KS (2014a) Melatonin reduces airway inflammation in ovalbumin-induced asthma. Immunobiology 219:901–908

    Article  CAS  Google Scholar 

  • Shin IS, Park JW, Shin NR, Jeon CM, Kwon OK, Lee MY, Kim HS, Kim JC, Oh SR, Ahn KS (2014b) Melatonin inhibits MUC5AC production via suppression of MAPK signaling in human airway epithelial cells. J Pineal Res 56:398–407

    Article  CAS  Google Scholar 

  • Stanford KR, Hadley SH, Barannikov I, Ajmo JM, Bahia PK, Taylor-Clark TE (2019) Antimycin A-induced mitochondrial dysfunction activates vagal sensory neurons via ROS-dependent activation of TRPA1 and ROS-independent activation of TRPV1. Brain Res 1715:94–105

    Article  CAS  Google Scholar 

  • Sunyer J, Basagaña X, Belmonte J, Antó JM (2002) Effect of nitrogen dioxide and ozone on the risk of dying in patients with severe asthma. Thorax 57:687–693

    Article  CAS  Google Scholar 

  • Sussan TE, Gajghate S, Chatterjee S, Mandke P, McCormick S, Sudini K, Kumar S, Breysse PN, Diette GB, Sidhaye VK, Biswal S (2015) Nrf2 reduces allergic asthma in mice through enhanced airway epithelial cytoprotective function. Am J Physiol Lung Cell Mol Physiol 309:L27–L36

    Article  CAS  Google Scholar 

  • Thomas KC, Roberts JK, Deering-Rice CE, Romero EG, Dull RO, Lee J, Yost GS, Reilly CA (2012) Contributions of TRPV1, endovanilloids, and endoplasmic reticulum stress in lung cell death in vitro and lung injury. Am J Physiol Lung Cell Mol Physiol 302:L111–L119

    Article  CAS  Google Scholar 

  • Uslusoy F, Nazıroğlu M, Çiğ B (2017) Inhibition of the TRPM2 and TRPV1 channels through hypericum perforatum in sciatic nerve injury-induced rats demonstrates their key role in apoptosis and mitochondrial oxidative stress of sciatic nerve and dorsal root ganglion. Front Physiol 8:335

    Article  Google Scholar 

  • Veres TZ, Rochlitzer S, Braun A (2009) The role of neuro-immune cross-talk in the regulation of inflammation and remodelling in asthma. Pharmacol Ther 122:203–214

    Article  CAS  Google Scholar 

  • Wallrapp A, Burkett PR, Riesenfeld SJ, Kim SJ, Christian E, Abdulnour RE, Thakore PI, Schnell A, Lambden C, Herbst RH et al (2019) Calcitonin gene-related peptide negatively regulates alarmin-driven type 2 innate lymphoid cell responses. Immunity 51:709–723.e706

    Article  CAS  Google Scholar 

  • Yu Q, Yu X, Zhong X, Ma Y, Wu Y, Bian T, Huang M, Zeng X (2020) Melatonin modulates airway smooth muscle cell phenotype by targeting the STAT3/Akt/GSK-3β pathway in experimental asthma. Cell Tissue Res 380:129–142

    Article  CAS  Google Scholar 

  • Zhang JH, Yang X, Chen YP, Zhang JF, Li CQ (2019) Nrf2 activator RTA-408 protects against ozone-induced acute asthma exacerbation by suppressing ROS and γδT17 cells. Inflammation 42:1843–1856

    Article  CAS  Google Scholar 

Download references

Funding

This work was funded by the National Natural Science Foundation of China (81903278), Hubei Provincial Department of Education Science Research Program (Q20191103) and Regular Undergraduate Institutions Nature Science Research Project of Guizhou Education Department (Technology top-notch talent support project QianjiaoheKYzi [2018] 083).

Author information

Author notes

  1. Yushan Chen and Xiaoyu Wu contributed equally to this work.

Authors and Affiliations

  1. Brain Science and Advanced Technology Institute, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China

    Yushan Chen, Xiaoyu Wu, Yan Zeng & Jinquan Li

  2. Hubei Province Key Laboratory of Occupational Hazard Identification and Control, School of Medicine, Wuhan University of Science and Technology, Wuhan, 430065, China

    Xu Yang & Jinquan Li

  3. Section of Environmental Biomedicine, Hubei Key Laboratory of Genetic Regulation and Integrative Biology, College of Life Sciences, Central China Normal University, Wuhan, 430079, China

    Xu Yang

  4. Department of Food Science and Engineering, Moutai Institute, Renhuai, 564507, China

    Xudong Liu

Authors
  1. Yushan Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xiaoyu Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Xu Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Xudong Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yan Zeng
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Jinquan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Jinquan Li, Yushan Chen, and Xu Yang conceived and designed the experiments. Xiaoyu Wu, Jinquan Li, and Xudong Liu performed the experiments. Jinquan Li, Yushan Chen, and Xu Yang analyzed the data. Yushan Chen, Yan Zeng, and Jinquan Li wrote the manuscript. Jinquan Li revised the manuscript. All authors have given approval to the final version of the manuscript.

Corresponding author

Correspondence to Jinquan Li.

Ethics declarations

Ethical approval

Animals were treated humanely and all experiments were conducted according to a protocol approved by the Office of Scientific Research Management of Central China Normal University (CCNU-IACUC-2017-012).

Consent to participate

Not applicable.

Consent to publish

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Responsible Editor: Mohamed M. Abdel-Daim

Publisher’s note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Chen, Y., Wu, X., Yang, X. et al. Melatonin antagonizes ozone-exacerbated asthma by inhibiting the TRPV1 channel and stabilizing the Nrf2 pathway. Environ Sci Pollut Res 28, 59858–59867 (2021). https://doi.org/10.1007/s11356-021-14945-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11356-021-14945-9

Keywords

Search

Navigation