Allergo-immunopathology mechanism of thymol-inhibiting airway remodeling in asthmatic mice by regulating TGF-β/Smad3 pathway

Main Article Content

Liyuan Zhang
Wenna Zhang
Yanan Wang
Pei Cai
Chaoran Li
Yan Shi
Seyyed Shamsadin Athari
Ailing Li

Keywords

Signaling Pathways, Asthma, T helper, Drug, Remodeling

Abstract


Allergic asthma is an important public health problem and is a complicated respiratory sickness that is characterized by bronchial inflammation, bronchoconstriction, and breathlessness. Asthma is orchestrated by type 2 immune response and remodeling is one of the important outputted problem in chronic asthma. Thymol is a naturally occurring monocyclic phenolic, it has a series of biological properties, and its immunomodulatory and anti-remodeling effects on allergic asthma were evaluated. The OVA-LPS-induced asthmatic mice were treated with thymol. Methacholine challenge test, eosinophil count, and levels of IL-4, IL-5, IL-13, and IL-33 in bronchoalveolar lavage fluid, total and OVA-specific IgE levels in serum, remodeling factors, gene expression of TGF-β, Smad2, Smad3, and lung histopathology were done. Treatment with thymol could control AHR, eosinophil percentage levels of Th2 cytokines and Igs, remodeling factors, expression of TGF-β, Smad2 and Smad3 genes, inflammation, goblet cell hyperplasia, and mucus production in asthmatic mice. Thymol can control asthma pathogens and related remodeling and fibrosis bio-factors and can be a potential treatment of asthma.


Abstract 280 | PDF Downloads 422 HTML Downloads 0 XML Downloads 4

References

1. Wenzel, SE. Asthma: Defining of the persistent adult phenotypes. Lancet. 2006;368:804–813. 10.1016/S0140-6736(06)69290-8

2. Montuschi, P. Pharmacotherapy of patients with mild persistent asthma: Strategies and unresolved issues. Front Pharmacol. 2011; 2:35. 10.3389/fphar.2011.00035

3. Zhang, Y, Li, S, Huang, S, Cao, L, Liu, T, Zhao, J, et al. IL33/ST2 contributes to airway remodeling via p-JNK MAPK/STAT3 signaling pathway in OVA-induced allergic airway inflammation in mice. Exp Lung Res. 2019; 45:65–75. 10.1080/01902148.2019.1611972

4. Cantani, A. and Micera, M. A study on 300 asthmatic children, 300 controls and their parents confirms the genetic transmission of allergy and asthma. Eur Rev Med Pharmacol. SCI. 2011; 15:1051–1056.

5. Vale, K. Targeting the JAK-STAT pathway in the treatment of ‘Th2-high’ severe asthma. Future Med Chem. 2016; 8:405–419. 10.4155/fmc.16.4

6. Zhiwei Wu, Entezar Mehrabi Nasab, Poonam Arora, Seyyed Shamsadin Athari. Study effect of probiotics and prebiotics on treatment of OVA-LPS-induced of allergic asthma inflammation and pneumonia by regulating the TLR4/NF-kB signaling pathway. J Transl Med. 2022; 20:130. 10.1186/s12967-022-03337-3

7. Narendra VT, Anamika S, Robin J, Monika K, Vishal A. Vitex negundo linn extract alleviates inflammatory aggravation and lung injury by modulating AMPK/PI3K/Akt/p38-NF-κB and TGF-β/Smad/Bcl2/caspase/LC3 cascade and macrophages activation in murine model of OVA-LPS induced allergic asthma. J Ethnopharmacol. 2021; 271:113894. 10.1016/j.jep.2021.113894

8. Akbar Mohammadi, Soleiman Mahjoub, Kamran Ghafarzadegan, Hamid Reza Nouri. Immunomodulatory effects of thymol through modulation of redox status and trace element content in experimental model of asthma. Biomed Pharmacother. 2018; 105:856–861. 10.1016/j.biopha.2018.05.154

9. El-Sayed el SM, Mansour AM, Abdul-Hameed MS. Thymol and carvacrol prevent doxorubicin-induced cardiotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol. 2016; 30(1):37–44. 10.1002/jbt.21740

10. Bahador Hajimohammadi, Seyyede Masoume Athari, Mohammad Abdollahi, Ghasem Vahedi, Seyyed Shamsadin Athari. Oral administration of acrylamide worsens the inflammatory responses in the airways of asthmatic mice through agitation of oxidative stress in the lungs. Front Immunol. 2020; 11:1940. 10.3389/fimmu.2020.01940

11. Masoume Athari S, Mehrabi Nasab E, Shamsadin Athari S. Study effect of ocimum basilicum seeds on mucus production and cytokine gene expression in allergic asthma mice model. Revue française d’allergologie. 2018; 58(7):489–493. 10.1016/j.reval.2018.08.003

12. Wenxin Wang, Zhaochuan Yang, Meixiang Li, Zhenhong Wang, Yanchun Shan, Zhenghai Qu. Six1 promotes epithelial-mesenchymal transition in bronchial epithelial cells via the TGFβ1/Smad signalling pathway. Int Arch Allergy Immunol. 2021; 182:479–488. 10.1159/000512873

13. Martin T Johnson, Cory Benson J, Trayambak Pathak, Ping Xin, Abagail S McKernan, Scott M. Emrich, et al. The airway smooth muscle sodium/calcium exchanger NCLX is critical for airway remodeling and hyperresponsiveness in asthma. J Biol Chem. 2022; 298(8):102259. 10.1016/j.jbc.2022.102259

14. Jun-xia Jiang, Yan Guan, Hui-juan Shen, Yong-liang Jia, Jian Shen, Lin-hui Zhang, et al. Inhibition of soluble epoxide hydrolase attenuates airway remodeling in a chronic asthma model. Eur J Pharmacol. 2020; 868:172874. 10.1016/j.ejphar.2019.172874

15. Rasha M Hussein, El-Shaimaa A Arafa, Sayed Abdel Raheem, Wafaa R Mohamed. Thymol protects against bleomycin-induced pulmonary fibrosis via abrogation of oxidative stress, inflammation, and modulation of miR-29a/TGF-β and PI3K/Akt signaling in mice. Life Sci. 2023; 314: 121256. 10.1016/j.lfs.2022.121256

16. Kexin Ma, Cailong Li, Jingbin Xu, Fei Ren, Xin Xu, Chaosheng Liu, et al. LncRNA Gm16410 regulates PM2.5-induced lung endothelial-mesenchymal transition via the TGF-β1/Smad3/p-Smad3 pathway. Ecotoxicol Environ Saf. 2020; 205:111327. 10.1016/j.ecoenv.2020.111327

17. Ying Zhou, Qirui Duan, Dong Yang. In vitro human cell-based models to study airway remodeling in asthma. Biomed Pharmacother. 2023; 159:114218. 10.1016/j.biopha.2023.114218

18. Feifei Chen, Kenji Ogawa, Xubao Liu, Teresa M Stringfield, Yan Chen. Repression of Smad2 and Smad3 transactivating activity by association with a novel splice variant of CCAAT-binding factor C subunit. Biochem J. 2002; 364:571–577. 10.1042/bj20011703

19. Ji Young Kang, Chin Kook Rhee, Ju Sang Kim, Chan Kwon Park, Seung Joon Kim, Sang Haak Lee, et al. Effect of tiotropium bromide on airway remodeling in a chronic asthma model. Ann Allergy Asthma Immunol. 2012; 109:29–35. 10.1016/j.anai.2012.05.005

20. Talha Ijaz, Konrad Pazdrak, Mridul Kalita, Rolf Konig, Sanjeev Choudhary, Bing Tian, et al. Systems biology approaches to understanding epithelial mesenchymal transition (EMT) in mucosal remodeling and signaling in asthma. World Allergy Organ J. 2014; 7:13. 10.1186/1939-4551-7-13

21. Daniel J. Bernard. Both SMAD2 and SMAD3 mediate activin-stimulated expression of the follicle-stimulating hormone—Subunit in mouse gonadotrope cells. Mol Endocrinol. 2004; 18(3):606–623. 10.1210/me.2003-0264

22. Bin Sun, Huiqiao Wu, Jiajia Lu, Rongcheng Zhang, Xiaolong Shen, Yifei Gu, et al. Irisin reduces bone fracture by facilitating osteogenesis and antagonizing TGF-β/Smad signaling in a growing mouse model of osteogenesis imperfecta. J Orthop Translat. 2023; 38:175–189. 10.1016/j.jot.2022.10.012

23. Rie Watanabe, Yuichiro Yamada, Yu Ihara, Yoshimichi Someya, Akira Kubota, Shinji Kagimoto, et al. The MH1 domains of Smad2 and Smad3 are involved in the regulation of the ALK7 signals. Biochem Biophys Res Commun. 1999; 254:707–712. 10.1006/bbrc.1998.0118

24. Taro Umezu, Satoshi Nakamura, Yuiko Sato, Tami Kobayashi, Eri Ito, Takaya Abe, et al. Smad2 and Smad3 expressed in skeletal muscle promote immobilization-induced bone atrophy in mice. Biochem Biophys Res Commun. 2021; 582:111e117. 10.1016/j.bbrc.2021.10.043

25. Moir LM, Burgess JK, Black JL. Transforming growth factor beta 1 increases fibronectin deposition through integrin receptor alpha 5 beta 1 on human airway smooth muscle. J Allergy Clin Immunol. 2008; 121:1034–1039. 10.1016/j.jaci.2007.12.1159

26. Ershun Zhou, Yunhe Fu, Zhengkai Wei, Yuqiang Yu, Xichen Zhang, Zhengtao Yang. Thymol attenuates allergic airway inflammation in ovalbumin (OVA)-induced mouse asthma. Fitoterapia. 2014; 96:131–137. 10.1016/j.fitote.2014.04.016

27. Qiongyao Zeng, Yuncheng Che, Yu Zhang, Mei Chen, Qiang Guo, Wenjing Zhang. Thymol isolated from thymus vulgaris L. inhibits colorectal cancer cell growth and metastasis by suppressing the Wnt/β-Catenin pathway. Drug Des Devel Ther. 2020:14 2535–2547. 10.2147/DDDT.S254218

28. Lan Yao, Guo Hou, Lu Wang, Xiao-shu Zuo, Zhou Liu. Protective effects of thymol on LPS-induced acute lung injury in mice. Microb Pathog. 2018: 116:8–12. 10.1016/j.micpath.2017.12.065

29. Minmin Huang, Entezar Mehrabi Nasab, Seyyed Shamsadin Athari. Immunoregulatory effect of mesenchymal stem cell via mitochondria signaling pathways in allergic asthma. Saudi J Biol Sci. 2021; 28:6957–6962. 10.1016/j.sjbs.2021.07.071

30. Wang, Z, DiDonato, JA, Buffa, J, Comhair, SA, Aronica, MA, Dweik, RA, et al. Eosinophil peroxidase catalyzed protein carbamylation participates in asthma, J Biol Chem. 2016; 291(42):22118–22135. 10.1074/jbc.M116.750034

31. El-Sayed, EM, Abd-Allah, AR, Mansour, AM, El-Arabey, AA. Thymol and carvacrol prevent cisplatin-induced nephrotoxicity by abrogation of oxidative stress, inflammation, and apoptosis in rats. J Biochem Mol Toxicol. 2015; 29(4):165–172. 10.1002/jbt.21681