INFLAMMATION CELL-MOLECULAR FEATURES AND SURVIVAL IN PATIENTS WITH OCCUPATIONAL CHRONIC OBSTRUCTIVE PULMONARY DISEASE FROM SILICA DUST EXPOSURE

Objective - to establish the inflammation features and 5-years survival in occupational chronic obstructive pulmonary disease (COPD) from silica dust exposure. Material and methods. It was an observational prospective cohort study. Occupational COPD patients ( n = 101) and healthy workers ( n = 51) exposed to silica dust enrolled. Comparison group - tobacco smokers with COPD ( n = 103). Control group - healthy people without occupational health risks ( n = 99). COPD was diagnosed according to GOLD 2011-2018 criteria. Groups were matched by length of service, smoking status, demographic characteristics. Levels of inflammatory cytokines, oxidative stress markers and metalloproteinases were measured in serum by enzyme-linked immunosorbent assay. Statistical analysis - ANCOVA and multiple linear regression. Survival was analyzed using Kaplan - Meier method and Cox proportional hazard regression. Results. Occupational COPD was characterized by high serum levels of monocyte chemoattractant protein 1 (MCP1), extracellular superoxide dismutase (SOD3), fibroblast growth factor 2 (FGF2) and 8-iso-prostaglandin F2α (8-iso-PGF2α). In healthy workers exposed to silica dust an increase in FGF2, МСР1 and SOD3 was revealed. In multiple regression models length of service and dust concentrations in the workplace air were associated with molecular factors. Inflammation features were associated with lung remodeling and function. Serum level of IL1β was associated with forced expiratory volume in 1 second (В = -3.4; р = 0.028), MMP 9 content - with residual volume ratio to total lung capacity (В = 1.3; р = 0.01) and FGF2 content - with diffusing lung capacity to CO (В = -2.4; р = 0.001). The 5-year cumulative death rate from pneumonia was higher in COPD due to dust when compared with tobacco smokers COPD (5 and 2 % respectively), while there was not differences in all cause survival. Multivariate analysis revealed that length of service, dust concentrations in the workplace air, serum concentration of М??1, MMP?9, FGF2 and 8-???-PGF2? are significantly associated with mortality. СР1, MMP 9, FGF2 and 8-изо-PGF2α are significantly associated with mortality. Conclusion. Occupational COPD from silica dust exposure is a specific endotype characterized by high risk of mortality from pneumonia. In workers exposed to dust for more than 10 years FGF2 is a perspective biomarker of high occupational COPD risk.

occupational chronic obstructive pulmonary disease, phenotype, endotype, survival, inorganic silica dust

1. Васильева О.С., Кравченко Н.Ю. Хроническая обструктивная болезнь легких как профессиональное заболевание: факторы риска и проблема медико-социальной реабилитации больных // Рос. мед. журн. 2015. 21. (5). 22-26.

2. Величковский Б.Т. Экологическая пульмонология (роль свободнорадикальных процессов). Екатеринбург: ЕМНЦ, 2003. 141 с.

3. Гайнитдинова В.В., Авдеев С.Н. Хроническая обструктивная болезнь легких с легочной гипертензией: особенности течения, выживаемость, предикторы летальности // Пульмонология. 2017. 27. (3). 357-365.

4. Измеров Н.Ф., Бухтияров И.В., Прокопенко Л.В., Шиган Е.Е. Реализация глобального плана действий ВОЗ по охране здоровья работающих в Российской Федерации // Мед. труда и пром. экология. 2015. (9). 4-10.

5. Косарев В.В., Жестков А.В., Бабанов С.А., Аверина О.М., Васюков П.А. Иммунопатогенетические особенности профессионального бронхита // Мед. труда и пром. экология. 2012. (9). 22-27.

6. Профессиональные заболевания органов дыхания: национальное руководство / ред. Н.Ф. Измеров, А.Г. Чучалин. М.: ГЭОТАР-Медиа, 2015. 792 с.

7. Чучалин А.Г., Айсанов З.Р., Чикина С.Ю., Черняк А.В., Калманова Е.Н. Федеральные клинические рекомендации Российского респираторного общества по использованию метода спирометрии // Пульмонология. 2014. (6). 11-24.

8. Celli B.R., Locantore N., Yates J., Tal-Singer R., Miller B.E., Bakke P., Calverley P., Coxson H., Crim C., Edwards L.D., Lomas D.A., Duvoix A., MacNee W., Rennard S., Silverman E., Vestbo J., Wouters E., Agustí A. Inflammatory biomarkers improve clinical prediction of mortality in chronic obstructive pulmonary disease // Am. J. Respir. Crit. Care Med. 2012. 185. (10). 1065-1072.

9. Chanda D., Otoupalova E., Smith S.R., Volckaert T., de Langhe S.P., Thannickal V.J. Developmental pathways in the pathogenesis of lung fibrosis // Mol. Aspects Med. 2018. https://www.sciencedirect.com/science/article/pii/S0098299718300712?via%3Dihub (дата обращения: 28.08.2018).

10. Chuchalin A.G., Khaltaev N., Antonov N.S., Galkin D.V., Manakov L.G., Antonini P., Murphy M., Solodovnikov A.G., Bousquet J., Pereira M.H. Demko I.V. Chronic respiratory diseases and risk factors in 12 regions of the Russian Federation // Int. J. Chron. Obstruct. Pulmon. Dis. 2014. 9. 963-974.

11. Churg A., Zhou S., Wang X., Wang R., Wright J.L. The role of interleukin-1beta in murine cigarette smoke-induced emphysema and small airway remodeling // Am. J. Respir. Cell. Mol. Biol. 2009. 40. (4). 482-490.

12. Duman D., Aksoy E., Agca M.C., Kocak N.D., Ozmen I., Akturk U.A., Gungor S., Tepetam F.M., Eroglu S.A., Oztas S., Karakurt Z. The utility of inflammatory markers to predict readmissions and mortality in COPD cases with or without eosinophilia // Int. J. Chron. Obstruct. Pulmon. Dis. 2015. 10. 2469-2478.

13. Fishwick D., Sen D., Barber C., Bradshaw L., Robinson E., Sumner J. Occupational chronic obstructive pulmonary disease: a standard of care // Occup. Med. (Lond.). 2015. 65. (4). 270-282.

14. Global Initiative for chronic obstructive lung disease. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease (2018 report). http://goldcopd.org/wp-content/uploads/2017/11/GOLD-2018-v6.0-FINAL-revised-20-Nov_WMS.pdf (дата обращения: 27.07.2018).

15. Hjalmarsen A., Brenn T., Jongsma Risberg M., Meisler Antonsen K., Kristiansen Benum E., Aaseboe U. Retrospective survival in elderly COPD patients receiving pulmonary rehabilitation; a study including maintenance rehabilitation // BMC Res. Notes. 2014. 7. 210.

16. Husebo G.R., Bakke P.S., Grønseth R., Hardie J.A., Ueland T., Aukrust P., Eagan T.M. Macrophage migration inhibitory factor, a role in COPD // Am. J. Physiol. Lung Cell. Mol. Physiol. 2016. 311. (1). L1-L7.

17. Kaźmierczak M., Ciebiada M., Pękala-Wojciechowska A., Pawłowski M., Nielepkowicz-Goździńska A., Antczak A. Evaluation of markers of inflammation and oxidative stress in COPD patients with or without cardiovascular comorbidities // Heart Lung Circ. 2015. 24. (8). 817-823.

18. Kranenburg A.R., Willems-Widyastuti A., Mooi W.J., Saxena P.R., Sterk P.J., de Boer W.I., Sharma H.S. Chronic obstructive pulmonary disease is associated with enhanced bronchial expression of FGF-1, FGF-2, and FGFR-1 // J. Pathol. 2005. 206. 28-38.

19. Mannino D.M., Tal-Singer R., Lomas D.A., Vestbo J., Graham Barr R., Tetzlaff K., Lowings M., Rennard S.I., Snyder J., Goldman M., Martin U.J., Merrill D., Martin A.L., Simeone J.C., Fahrbach K., Murphy B., Leidy N., Miller B. Plasma fibrinogen as a biomarker for mortality and hospitalized exacerbations in people with COPD // Chronic Obstr. Pulm. Dis. (Miami). 2015. 2. (1). 23-34.

20. Montaño M., Cisneros J., Ramírez-Venegas A., Pedraza-Chaverri J., Mercado D., Ramos C., Sansores R.H. Malondialdehyde and superoxide dismutase correlate with FEV1 in patients with COPD associated with wood smoke exposure and tobacco smoking // Inhal. Toxicol. 2010. 22. (10). 868-874.

21. Paulin L.M., Diette G.B., Blanc P.D., Putcha N., Eisner M.D., Kanner R.E., Belli A.J., Christenson S., Tashkin D.P., Han M., Barr R.G., Hansel N.N. Occupational exposures are associated with worse morbidity in patients with chronic obstructive pulmonary disease // Am. J. Respir. Crit. Care Med. 2015. 191. (5). 557-565.

22. Pavord I.D., Lettis S., Locantore N., Pascoe S., Jones P.W., Wedzicha J.A., Barnes N.C. Blood eosinophils and inhaled corticosteroid/long-acting β-2 agonist efficacy in COPD // Thorax. 2016. 71. (2). 118-125. Suissa S., Dell’Aniello S., Ernst P. Long-term natural history of chronic obstructive pulmonary disease: severe exacerbations and mortality // Thorax. 2012. 67. (11). 957-963. The Institute for Health Metrics and Evaluation (IHME). GBD Compare data viz. https://vizhub.healthdata.org/gbd-compare/ (дата обращения: 27.07. 2018). Victoni T., Gleonnec F., Lanzetti M., Tenor H., Valença S., Porto L.C., Lagente V., Boichot E. Roflumilast N-oxide prevents cytokine secretion induced by cigarette smoke combined with LPS through JAK/STAT and ERK1/2 inhibition in airway epithelial cells // PLoS One. 2014. 9. (1). e85243.