Skip to main content

Advertisement

SpringerLink
Log in

Relationship of endoplasmic reticulum stress with the etiopathogenesis of chronic tonsillitis and tonsillar hypertrophy in pediatric patients: a prospective, parallel-group study

  • Original Article
  • Published:
Molecular Biology Reports Aims and scope Submit manuscript

Abstract

Objectives

Tonsil tissue is a very important component of the human immunity system, contributing to the functioning of the cellular and humoral defence system, especially in childhood. The endoplasmic reticulum (ER) is an organelle that has a very important function in the balanced functioning of cells, in which the accumulation of a cellular protein called ER stress occurs in case of dysfunction. ER stress influences the pathogenesis of many diseases and immune system functions. We aimed to investigate the relation between the diseases of tonsil tissue and ER stress response to elucidate the mechanisms of diseases related with the immune system.

Methods

A prospective study was conducted in 46 children aged between 2 and 16 years who underwent tonsillectomy for chronic tonsillitis or tonsillar hypertrophy. Tonsil tissue was separated into two groups according to their size and evaluated in terms of ER stress markers and apoptosis markers by Real-time PCR and Western blot analysis.

Results

The ΔCT levels of ER stress markers (ATF4, ATF6, CHOP, GRP78, EIF2AK3, ERN1, GRP94) were greater in children with chronic tonsillitis (p < 0.005). In contrast, the tonsillar hypertrophy group had greater ΔCT levels of apoptosis markers (BAX, BCL-2) according to the Real-time PCR method (p < 0.005). According to the Western blot analysis, the normalized levels of ATF4, ATF6, CHOP, GRP78, and ERN1 genes were found greater in the chronic tonsillitis group than the tonsillar hypertrophy group. There was no difference between the two groups in terms of normalized BCL-2 and BAX levels by Western blot analysis.

Conclusion

This is the first study in the literature investigating the effect of the ER stress pathway on the etiopathogenesis of tonsil diseases. It was concluded that the ER stress pathway plays a role in the etiopathogenesis of chronic tonsillitis. Investigating the relationship between ER stress and structures such as the tonsil tissue that make up the immune system can help create new treatment strategies.

Clinical Trial Registration

Trial Registration ClinicalTrials.gov Identifier: NCT04653376.

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

Similar content being viewed by others

References

  1. Ogra PL (2000) Mucosal immune response in the ear, nose and throat. Pediatr Infect Dis J 19(5 Suppl):S4-8. https://doi.org/10.1097/00006454-200005001-00002

    Article  CAS  PubMed  Google Scholar 

  2. Yan Y, Song Y, Liu Y, Su J, Cui L, Wang J, Geng J, Liu X, Shi Y, Quan S, Hang A, Zuo L (2019) Short and long-term impacts of adenoidectomy with/without tonsillectomy on immune function of young children <3 years of age A cohort study. Medicine (Baltimore) 98(19):e15530. https://doi.org/10.1097/MD.0000000000015530

    Article  Google Scholar 

  3. Alan D, Kornblut A (1991) Non neoplastic diseases of the tonsils and adenoids. In: Paparella M, Shumrick DA, Gluckman JL, Meyerhof WL (eds) Otorhinolaryngology, vol 3, 3rd edn. W. B. Sounders Company, New York, pp 2129–47

    Google Scholar 

  4. Hata M, Asakura K, Saito H, Morimoto K, Kataura A (1996) Profile of immunoglobulin production in adenoid and tonsil lymphocytes. Acta Otolaryngol Suppl 523:84–86

    CAS  PubMed  Google Scholar 

  5. Palomares O, Rückert B, Jartti T, Kücüksezer UC, Puhakka T, Gomez E, Fahrner EB, Speiser A, Jung A, Kwok WW, Kalogjera L, Akdis M, Akdis CA (2012) Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance. J Allergy Clin Immunol 129(2):510–520. https://doi.org/10.1016/j.jaci.2011.09.031

    Article  CAS  PubMed  Google Scholar 

  6. So JS (2018) Roles of endoplasmic reticulum stress in ımmune responses. Mol Cells 41(8):705–716. https://doi.org/10.14348/molcells.2018.0241

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. González-Quiroz M, Blondel A, Sagredo A, Hetz C, Chevet E, Pedeux R (2020) When endoplasmic reticulum proteostasis meets the DNA damage response. Trends Cell Biol 30(11):881–891. https://doi.org/10.1016/j.tcb.2020.09.002

    Article  CAS  PubMed  Google Scholar 

  8. Amodio G, Moltedo O, Fasano D, Zerillo L, Oliveti M, Di Pietro P, Faraonio R, Barone P, Pellecchia MT, De Rose A (2019) PERK-mediated unfolded protein response activation and oxidative stress in PARK20 fibroblasts. Front Neurosci Switz 27(13):673. https://doi.org/10.3389/fnins.2019.00673

    Article  Google Scholar 

  9. Gardner BM, Walter P (2011) Unfolded proteins are Ire1-activating ligands that directly induce the unfolded protein response. Science 333(6051):1891–1894. https://doi.org/10.1126/science.1209126

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Urra H, Dufey E, Lisbona F, Rojas-Rivera D (1833) Hetz C (2013) When ER stress reaches a dead end. Biochim Biophys Acta 12:3507–3517. https://doi.org/10.1016/j.bbamcr.2013.07.024

    Article  CAS  Google Scholar 

  11. Puthalakath H, Oeilly LA, Gunn P, Lee L, Kelly PN, Huntington ND, Hughes PD, Michalak EM, McKimm-Breschkin J, Motoyama N et al (2007) ER stress triggers apoptosis by activating BH3-only protein Bim. Cell 129(7):1337–49. https://doi.org/10.1016/j.cell.2007.04.027

    Article  CAS  PubMed  Google Scholar 

  12. Wang S, Kaufman RJ (2012) The impact of the unfolded protein response on human disease. J Cell Biol 197(7):857–67. https://doi.org/10.1083/jcb.201110131

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Friedman M, Tanyeri H, Rosa ML, Landsberg R, Vaidyanathan K, Pieri S, Caldarelli D (1999) Clinical predictors of obstructive sleep Apnea. Laryngoscope 109(12):1901–1907. https://doi.org/10.1097/00005537-199912000-00002

    Article  CAS  PubMed  Google Scholar 

  14. Rio DC, Ares MJ, Hannon GJ, Nilsen TW (2010) Purification of RNA using TRIzol (TRI reagent). Cold Spring Harb Protoc. https://doi.org/10.1101/pdb.prot5439

    Article  PubMed  Google Scholar 

  15. Nami B, Ghasemi-Dizgah A, Vaseghi A (2016) Overexpression of molecular chaperons GRP78 and GRP94 in CD44hi/CD24lo breast cancer stem cells. Bioimpacts 6(2):105–110. https://doi.org/10.15171/bi.2016.16

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Onal M, Yılmaz T, Bilgic E, Müftüoğlu SF, Kuşçu O, Günaydın RO (2015) Apoptosis in chronic tonsillitis and tonsillar hypertrophy. Int J Pediatr Otorhinolaryngol 79(2):191–195. https://doi.org/10.1016/j.ijporl.2014.12.005

    Article  PubMed  Google Scholar 

  17. Liu X, Liu JK (2020) Tanshinone I induces cell apoptosis by reactive oxygen species-mediated endoplasmic reticulum stress and by suppressing p53/DRAM-mediated autophagy in human hepatocellular carcinoma. Artif Cells Nanomed Biotechnol 48(1):488–497. https://doi.org/10.1080/21691401.2019.1709862

    Article  CAS  PubMed  Google Scholar 

  18. Onal M, Yılmaz T, Bilgiç E, Müftüoğlu S, Sözen T, Bajin MD (2015) Possible role of apoptosis in pathogenesis of adenoid hypertrophy and chronic adenoiditis: prospective case-control study. Auris Nasus Larynx 42(6):449–452. https://doi.org/10.1016/j.anl.2015.04.012

    Article  PubMed  Google Scholar 

  19. Onal M, Onal O, Turan A (2021) Can secondary lymphoid organs exert a favorable effect on the mild course of COVID-19 in children? Acta Otolaryngol 141(1):83–84. https://doi.org/10.1080/00016489.2020.1814965

    Article  CAS  PubMed  Google Scholar 

  20. Funakoshi U, Yonekura S, Iinuma T, Arimoto Y, Nakano A, Yamaide A, Tomiita M, Hoshioka A, Sakurai D, Okamoto Y (2021) The influence of tonsillectomy on allergic diseases in pediatric patients. Int J Pediatr Otorhinolaryngol 140:110503. https://doi.org/10.1016/j.ijporl.2020.110503

    Article  PubMed  Google Scholar 

  21. Ji EH, Elzakra N, Chen W, Cui L, Lee ES, Sun B, Messadi D, Xia T, Zhu Y, Hu S (2019) E-cigarette aerosols induce unfolded protein response in normal human oral keratinocytes. J Cancer 10(27):6915–6924. https://doi.org/10.7150/jca.31319

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Liu G, Guo T, Zhang Y, Liu N, Chen J, Chen J, Zhang J, Zhao J (2017) Apoptotic pathways of macrophages within osteolytic interface membrane in periprosthestic osteolysis after total hip replacement. APMIS 125(6):565–578. https://doi.org/10.1111/apm.12679

    Article  CAS  PubMed  Google Scholar 

  23. Shin HS, Ryu ES, Oh ES, Kang DH (2015) Endoplasmic reticulum stress as a novel target to ameliorate epithelial-to-mesenchymal transition and apoptosis of human peritoneal mesothelial cells. Lab Invest 95(10):1157–1173. https://doi.org/10.1038/labinvest.2015.91

    Article  CAS  PubMed  Google Scholar 

  24. Bae S, Kim M-K, Kim HS, Moon Y-A (2020) Arachidonic acid induces ER stress and apoptosis in HT-29 human colon cancer cells. Anim Cells Syst (Seoul) 24(5):260–266. https://doi.org/10.1080/19768354.2020.1813805

    Article  CAS  Google Scholar 

  25. Wang Y-Y, Lee K-T, Lim MC, Choi JH (2020) TRPV1 antagonist DWP05195 ınduces ER stress-dependent apoptosis through the ROS-p38-CHOP pathway in human ovarian cancer cells. Cancers 12(6):1702. https://doi.org/10.3390/cancers12061702

    Article  CAS  PubMed Central  Google Scholar 

  26. Liu C, Yan D-Y, Wang C, Ma Z, Deng Y, Liu W, Xu B (2020) Manganese activates autophagy to alleviate endoplasmic reticulum stress-induced apoptosis via PERK pathway. J Cell Mol Med 24(1):328–341. https://doi.org/10.1111/jcmm.14732

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Selcuk University Scientific Research Projects Coordination Unit under Grant number 19401029. We would like to express our gratitude to Prof. Neslihan Saltalı from Ordu University for her help in the statistical analysis part.

Author information

Authors and Affiliations

  1. Department of Otolaryngology, Faculty of Medicine, Selcuk University, Konya, Turkey

    Merih Onal, Mete Kaan Bozkurt, Cagdas Elsurer & Omer Erdur

  2. Department of Medical Genetics, Faculty of Medicine, Selcuk University, Konya, Turkey

    Nadir Kocak & Fahrettin Duymus

  3. Department of Outcomes Research, Cleveland Clinic Anesthesiology Institute, Cleveland, OH, USA

    Ozkan Onal

  4. Department of Anesthesiology and Reanimation, Faculty of Medicine, Selcuk University, Konya, Turkey

    Ozkan Onal

Authors
  1. Merih Onal
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nadir Kocak
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fahrettin Duymus
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mete Kaan Bozkurt
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Cagdas Elsurer
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Omer Erdur
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Ozkan Onal
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Conceiving and designing the study; or collecting the data; or analyzing and interpreting the data; MO, NK, FD, CE, OE, OO, writing the manuscript or providing critical revisions that are important for the intellectual content; MO, OO, MKB approving the final version of the manuscript; MO, MKB, CE, OE, Relationship of endoplasmic reticulum stress with the etiopathogenesis of chronic tonsillitis and tonsillar hypertrophy in pediatric patients: a prospective, parallel-group study.

Corresponding author

Correspondence to Merih Onal.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee (Selcuk University Faculty of Medicine Clinical Researches Ethics Committee) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. Ethics approval for the study was obtained from the Clinical Research Ethics Committee of Selcuk University Medical Faculty (Ref No: 2018/329). Our study was supported by the Selcuk University Scientific Research Projects Coordination Unit (Project Number: 19401029). After obtaining informed consent from the parents of the patients to be included in the study, we conducted our study by the ethical standards stated in the 1964 Helsinki Declaration. Human tonsil samples used in this study were obtained from tonsillectomy patients in Selcuk University, Faculty of Medicine Hospital, Department of Otolaryngology between the dates of November 2018 and August 2019.

Consent to participate

Informed consent was obtained from all patients’ parents.

Additional information

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

Onal, M., Kocak, N., Duymus, F. et al. Relationship of endoplasmic reticulum stress with the etiopathogenesis of chronic tonsillitis and tonsillar hypertrophy in pediatric patients: a prospective, parallel-group study. Mol Biol Rep 48, 5579–5586 (2021). https://doi.org/10.1007/s11033-021-06579-4

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11033-021-06579-4

Keywords

Search

Navigation