Features of immune regulation and cytokine profile in employees of a potash ore processing plant associated with polymorphism of the MMP9 836A>G gene

Introduction. The improvement of methodological approaches to identify the indicator indicators of the fine cellular-molecular profile of immune regulation and genetic polymorphism will optimize the implementation of measures for the early diagnosis and prevention of professionally caused diseases.

The aim of the study to research the features of cytokine immune regulation in employees of a potash ore processing enterprise associated with polymorphism of the MMP9 836A>G matrix metalloproteinase gene (rs17576).

Materials and methods. The authors have examined 64 employees of a potash ore processing enterprise working under the influence of harmful production factors, including dust factor. The comparison group consisted of 56 employees from the administrative staff. The researchers determined immunoglobulins in the radial immunodiffusion reaction. They studied the cytokine content by solid-phase enzyme immunoassay. Genotyping was performed by polymerase chain reaction in real time.

Results. Immunological examination of the main production workers revealed activation of the humoral link in IgG content in 50% of the examined and expression of mediators of proinflammatory cytokine regulation — VEGF by 1.28 times, IL‑1beta by 1.29 times, IL-6 by 1.58 times relative to the comparison group, associated with polymorphic changes in the matrix metallopriteinase-9 gene. The carriage of the variant G*836A>G allele of the MMP9 gene was significantly associated with increased VEGF expression (1.4 times) relative to the workers of the comparison group (mainly carriers of the AA genotype of the MMP9 gene), which allows us to consider the G allele as a marker of sensitivity of the examined group of workers of the main production of the potash ore enrichment enterprise (OR=1.73; 95% CI=1.03–2.93), which forms the risk of lung fibrosis under the influence of dust factor.

Limitations. The present study requires further study of the issue and verification of the data obtained due to the limited size of the sample examined.

Conclusion. The authors established a reliable association of VEGF expression with the variant allele G*836A>G of the MMR9 gene (OR=1.73; 95% CI=1.03–2.93), which indicates a pathogenetic relationship of the immune (cytokine) «storm» with remodeling of extracellular matrix structures and the formation of further fibrous changes in mucous membranes, as one of the proposed mechanisms of the development of production-related lung pathology associated with the dust factor in employees of a potash ore processing enterprise. Timely diagnostic methodological approaches to the identification of cytokine and genetic profile indicators allow us to substantiate the hypothesis of the formation of lung production pathology and recommend personalized programs for early diagnosis and prevention of health disorders of employees of the main production of the potash ore processing enterprise.

Ethics. All surveyed employees gave informed consent to participate in the study. The study was carried out in accordance with the Helsinki Declaration of the World Medical Association (revised 2013). The protocol of the study was approved by the Biomedical Ethics Committee of the local Ethical Committee of the Federal Scientific Center for Medical and Preventive Health Risk Management Technologies No. 5 dated 05/15/2023.

Contribution:
Starkova K.G. — the concept and design of the study, collection and processing of material, writing the text;
Dolgikh O.V. — the concept and design of the study, editing, responsibility for the integrity of all parts of the article;
Alekseev V.B. — the concept and design of the study, editing, responsibility for the integrity of all parts of the article;
Legostaeva T.A. — collection and processing of material, writing the text;
Kazakova O.A. — collection and processing of material.

Funding. The study had no funding.

Conflict of interests. The authors declare the absence of obvious and potential conflicts of interests in connection with the publication of this article.

Received: 21.05.2024 / Accepted: 10.06.2024 / Published: 31.07.2024

1. Babanov S.A., Budash D.S. Evaluation and prediction of respiratory disorders in lung diseases associated with exposure to fibrogenic aerosols. Meditsina neotlozhnykh sostoyaniy. 2016; 2(73): 120–127 (in Russian).

2. Lipińska-Ojrzanowska A, Marcinkiewicz A, Walusiak-Skorupa J. Usefulness of biomarkers in work-related airway disease. Curr. Treat. Options Allergy. 2017; 4(2): 181–190. https://doi.org/10.1007/s40521-017-0121-9

3. Zaitseva N.V., Zemlianova M.A., Dolgikh О.V. Genomic, transcriptomic and proteomic technologies as a modern tool for diagnostics of health disorders associated with the impact of environmental factors. Gigiena i sanitariya. 2020; 99(1): 6–12. https://elibrary.ru/pipsea (in Russian).

4. Strizhakov L.A., Babanov S.A., Budash D.S., Lebedeva M.V., Baikova A.G., Vostroknutova M.Yu. et al. Immunological features and prognosis in modern forms of occupational lung diseases. Med. Truda i Prom. Ekol. 2020; 60(2): 81–88. https://doi.org/10.31089/1026-9428-2020-60-2-81-88 (in Russian)

5. Cui N., Hu M., Khalil R.A. Biochemical and biological attributes of matrix metalloproteinases. Prog. Mol. Biol. Transl. Sci. 2017; 147: 1–73. https://doi.org/10.1016/bs.pmbts.2017.02.005

6. Shadrina A.S., Tereshkina I.V., Plieva Ya.Z., Kushlinsky D.N., Utkin D.O., Morozov A.A. et al. Matrix metalloproteinases: structure, functions and genetic polymorphism. Patogenez. 2017; 15(2): 14–23. https://doi.org/10.25557/GM.2017.2.7297 (in Russian).

7. Babanov S.A., Strizhakov L.A., Lebedeva M.V., Fomin V.V., Budash D.S., Baikova A.G. Pneumoconiosises: modern view. Terapevt. Arkh. 2019; 91(3): 107–113. https://doi.org/10.26442/00403660.2019.03.000066 (in Russian).

8. Shliapnikov D.M., Shur P.Z., Vlasova E.M., Alexeyev V.B., Lebedeva T.M. Occupational risk of cardiovascular diseases in workers engaged into underground mining. Med. truda i prom. ekol. 2015; (8): 6–9.

9. Zhou H.Y., Sui H., Zhao Y.J., Qian H.J., Yang N., Liu L. et al. The impact of inflammatory immune reactions of the vascular niche on organ fibrosis. Front. Pharmacol. 2021; 12: 750509. https://doi.org/10.3389/fphar.2021.750509

10. Kazitskaya A.S., Mikhailova N.N., Zhukova A.G., Gorokhova L.G. Immune mechanisms underlying occupational bronchopulmonary diseases due to dust. Med. truda i prom. ekol. 2018; 6: 33–38. https://doi.org/10.31089/1026-9428-2018-6-33-38 (in Russian).

11. Bolourani S., Brenner M., Wang P. The interplay of DAMPs, TLR4, and proinflammatory cytokines in pulmonary fibrosis. J. Mol. Med. (Berl). 2021; 99(10): 1373–1384. https://doi.org/10.1007/s00109-021-02113-y

12. Shadrina A.S., Plieva Y.Z., Kushlinskiy D.N., Morozov A.A., Filipenko M.L., Chang V.L. et al. Classification, regulation of activity, and genetic polymorphism of matrix metalloproteinases in health and disease. Almanac of Clinical Medicine. 2017; 45(4): 266–279. https://doi.org/10.18786/2072-0505-2017-45-4-266-279 (in Russian).

13. Robert S., Gicquel T., Victoni T., Valença S., Barreto E., Bailly-Maître B. et al. Involvement of matrix metalloproteinases (MMPs) and inflammasome pathway in molecular mechanisms of fibrosis. Biosci. Rep. 2016; 36(4): e00360. https://doi.org/10.1042/BSR20160107

14. Vempati P., Popel A.S., Mac Gabhann F. Extracellular regulation of VEGF: isoforms, proteolysis, and vascular patterning. Cytokine Growth Factor Rev. 2014; 25(1): 1–19. https://doi.org/10.1016/j.cytogfr.2013.11.002

15. Laddha A.P., Kulkarni Y.A. VEGF and FGF-2: Promising targets for the treatment of respiratory disorders. Respir. Med. 2019; 156: 33–46. https://doi.org/10.1016/j.rmed.2019.08.003

16. Zou F., Zhang J., Xiang G., Jiao H., Gao H. Association of matrix metalloproteinase 9 (MMP-9) polymorphisms with asthma risk: a meta-analysis. Can. Respir. J. 2019; 2019: 9260495. https://doi.org/10.1155/2019/9260495

17. Grzela K., Zagórska W., Krejner A., Litwiniuk M., Zawadzka-Krajewska A., Kulus M. et al. Polymorphic variants 279R and 668Q augment activity of matrix metalloproteinase-9 in breath condensates of children with asthma. Arch. Immunol. Ther. Exp. (Warsz). 2016; 5(2): 183–187. https://doi.org/10.1007/s00005-016-0412-z