Email this article THE CONTENT OF CYTOKINES REGULATING INFLAMMATION IN NASAL FLUSHING IN CHRONIC RHINOSINUSITIS IN ELDERLY AND SENILE PERSONS
- Authors: Tarasova N.V.1, Sokolova M.V.2, Belan E.B.1, Gorshenin А.V.3
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Affiliations:
- Volgograd State Medical University
- Volgograd Regional Clinical Hospital No. 1
- FSUE Research Institute of Hygiene, Toxicology and Occupational Pathology of the Federal Medical and Biological Agency of Russia
- Section: Original Studies
- URL: https://aspvestnik.ru/2410-3764/article/view/568785
- DOI: https://doi.org/10.35693/AVP568785
- ID: 568785
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Abstract
ABSTRACT
BACKGROUND. Chronic rhinosinusitis is a heterogeneous sinonasal inflammatory disease with constant symptoms and recurrent exacerbations, which affects about 10% of the world's population. Age-related changes in the nasal mucosa (involutive immunodeficiency, atrophic changes, etc.) can affect the course of the inflammatory process, which, in turn, should be borne in mind when planning therapeutic interventions.
AIMS - to study the features of local production of IL-4, IL-6, IL-8, IL-10 in elderly and senile persons with chronic rhinosinusitis.
MATERIALS AND METHODS. The study included patients aged 45 to 90 years with a confirmed diagnosis of "chronic rhinosinusitis" in the acute stage, who gave written informed consent to the study. The exclusion criteria were: age up to 45 years; allergic rhinitis; primary immunodeficiency; smoking; oncological disease of any organ system; chronic polypous rhinosinusitis; acute (exacerbation of chronic) diseases of other localization; vaccination; use of immunotropic drugs for 3 months before the start of the study. The scope of the laboratory examination included determination of the concentration of cytokines IL-4, IL-6, IL-8, IL-10 in nasal secretions by enzyme immunoassay.
RESULTS. The analysis of the determined values showed that the maximum level of IL-4 was determined in younger persons with rhonic rhinosinusitis 45-59 years old compared with older persons. In our study, the maximum content of IL-6 occurred in a group of patients aged 75-90 years, while the cytokine level significantly exceeded IL-6 in a group of healthy age-related patients, which indicates a more pronounced inflammatory reaction in patients of the oldest group with chronic rhinosinusitis. Cytokine levels above 600 pg/ml were found mainly in patients with chronic rhinosinusitis. Patients of group 4 had high IL-10 values and their values went beyond the range of the comparison groups.
CONCLUSION. The maximum level of macrophage-monocytic cytokines (IL-6 and IL-8) and anti-inflammatory IL-10 is determined in nasal flushing in patients with chronic rhinosinusitis aged 75-90 years, the highest detectable values of IL-4 are characteristic of patients aged 45-59 years.
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Introduction:
Chronic rhinosinusitis (CRS) is a heterogeneous sinonasal inflammatory disease with persistent symptoms and recurrent exacerbations that affects about 10% of the population worldwide [1]. Age-related changes in the nasal mucosa (involutive immunodeficiency, atrophic changes, etc.) can affect the course of the inflammatory process, which, in turn, should be taken into account when planning therapeutic interventions.
Despite the large contingent of patients and the interest of clinicians, little is known about the etiology, course, and results of CRS treatment in patients over 65 years of age, but the problem deserves it.
A Russian epidemiological study showed that the incidence of CRS in patients over 60 years of age almost doubled compared to with young patients aged 19 to 39 years [2].
Important information about the state of the nasal mucosa is provided by the local level of production of cytokines as factors that generate and modulate the interaction of cells of the immune system with each other and with extra-immune organs and tissues.
There has been a recent trend towards an increase in the incidence of recurrent chronic sinusitis, with older patients potentially more susceptible. In the elderly, reduced immunity to infections and the presence of comorbidities may lead to a more severe clinical course of chronic rhinosinusitis. Despite the availability of diagnostic criteria for the disease and recommendations for managing patients, obtaining new information about the pathogenetic features of the process caused by age-related changes will contribute to the optimization and individualization of treatment for each specific patient.
Purpose:
To study the features of local production of IL-4, IL-6, IL-8, IL-10 in elderly and senile patients with CRS.
Materials and methods:
The work is a one-time observational comparative study in parallel groups and is of an applied nature.
The work was approved by the local ethical committee of the VolgGMU (minutes No. 8 - 2019, meeting of the LEC dated April 10, 2019). In the course of the study, the informed consent of the patients was obtained in accordance with the established form. The work was supported by the intrauniversity grant No. 2127-KO from Volgograd State Medical University.
The study included patients aged 45 to 90 years with a confirmed diagnosis of chronic rhinosinusitis in the acute stage, who gave written informed consent to the study. The diagnosis of CRS was established in accordance with the federal clinical guidelines for the diagnosis and treatment of chronic rhinosinusitis [3].
The exclusion criteria were: age under 45; allergic rhinitis; primary immunodeficiency; smoking; cancer of any organ system; chronic polyposis rhinosinusitis; acute (exacerbation of chronic) diseases of other localization; vaccination; use of immunotropic drugs within 3 months before the start of the study.
From the number of patients included in the study (n=112), the following groups were formed: group 1 (comparison group 1) - patients without CRS aged 60-74 years (17/112); group 2 - patients without CRS aged 75-90 years (8/112); group 3 - patients with CRS aged 60-74 years (23/112); group 4 - patients with CRS aged 75-90 years (32/112); group 5 (comparison group 2) - patients with CRS aged 45-59 years (32/112)).
The material was taken with the patient in a sitting position with the head tilted back. To obtain a flush, 5 ml of a warm sterile isotonic sodium chloride solution was injected into the nasal cavity into both nasal passages alternately with a disposable syringe. The lavage fluid from both nasal passages was collected through a funnel into one sterile tube [4]. The concentration of cytokines IL-4, IL-6, IL-8, IL-10 (reagents of OOO Vector Best, Novosibirsk, Russia) was determined by enzyme immunoassay.
The obtained results were statistically processed using the Statistica 10.0 software package (StatSoft, USA). The Shapiro-Wilk test was used to check the normality of the distribution of indicators. With a non-perimetric distribution of indicators, the median value with an interquartile range (Me [Q 1-Q3]) was used to quantify the indicators. To assess the significance of differences between groups, the Kruskall-Wallis criterion was used, to compare frequencies, the F-test (Fisher's criterion). Statistically significant were considered differences at p<0.05.
Results:
In the course of the study, the results obtained are shown in Table No. 1.
Table 1. The level of cytokines in the nasal wash in patients with CRS aged 45-90 years.
Indicator, unit of measurement | Thresholds | 1 group n=17 | 2 group n=8 | 3 group n=26 | 4 group n=36 | 5 group n=32 | p | |
IL-4, pg/ml | 0,4 | P2-3=0,045 P3,4-5=0,039 | ||||||
IL-6, pg/ml | 0,5 | 32,6[0-736] | P1-4=0,047 P2-4=0,028 | |||||
IL-8, pg/ml | 2,0 | P1-4=0,038 | ||||||
IL-10, pg/ml | 1,0 | P1-4=0,049 P3-4=0,032 | ||||||
In general, there were no significant differences in local IL-4 production between the groups. At the same time, 48.8% (46/112) of patients had a cytokine level below the threshold level (Fig. 1, Fig. 1.1.). Analysis of the determined values showed that the maximum level of IL-4 was determined in younger persons with CRS aged 45-59 years compared with older persons. It is noteworthy that in elderly and senile patients, regardless of the presence of CRS, all values are below the median in the 1st comparison group (5 pg/ml) (Table 1). On the contrary, the level of cytokine in patients of mature age with CRS was significantly higher than in groups 3 and 4 (p 3.4-5=0.039), while the values exceeding the level of IL-4 in patients of groups 1 and 2 were Me 1, 04 [0-12] pg/ml for all values and Me 11.4 [5-12.6] pg/ml for detectable (above threshold) values. In elderly patients, the values were out of range in the comparison group, while about half (18 out of 32) of the values in group 5 were maximum. And values above 10 pg/ml were significantly more common in the group than in others.
IL-6 is an early pro-inflammatory cytokine of macrophage-monocyte origin, the main function of which is to induce an acute inflammatory response. In our study, the maximum content of IL-6 occurred in the group of patients aged 75-90 years with CRS, while the level of cytokine significantly exceeded (Fig. 2, Fig. 2.2.) the levels of IL-6 in the group of aged patients without CRS (p2 -4=0.028), which indicates a more pronounced inflammatory response in patients of the oldest group with CRS. Analysis of values above the threshold level showed the same pattern.
IL-8 is a non-specific marker of chronic inflammation of the nasal mucosa. In patients of the 4th group, the nasal secretion had the maximum values of IL-8 (Me 723.04 [590-978.9] pg/ml). Cytokine levels above 600 pg/ml occurred mainly in patients with CRS (90.9% VS 30.2%, p=0.038 in comparison groups 1-2) (Fig. 3).
When analyzing the level of IL-10, it turned out that lower values were found in patients of group 3 relative to other groups (Table 1, Fig. 4, Fig. 4.4.). Group 4 patients had high levels of IL-10 and their values were outside the range of the comparison groups. Undetectable values occurred with a comparable frequency (Table 1).
Discussion:
In general, the present study showed that the frequency of the determined values of all cytokines is comparable in all groups.
The system of pro-inflammatory cytokines in our work is represented by IL-6 and IL-8. They are predominantly of monocyte-macrophage origin and play a significant role in the implementation of innate immunity reactions and the induction of the inflammatory process.
IL-6, being an early pro-inflammatory cytokine, in addition to inducing the synthesis of acute-phase proteins in the liver and participating in the development of a hyperthermic reaction, plays an important role in the process of tissue remodeling, including damage to the epithelial barrier and fibrosis. Taking into account the presence of age-related features of immunity in the elderly and senile age, it seems appropriate to study the local production of cytokines during an acute inflammatory process in people of different ages, as well as immunosenescence - a chronic systemic inflammation called "inflammatory aging", characterized by an increase in the level of IL-6 and TNF-α in blood serum with age [5].
Another cytokine of monocyte-macrophage origin is IL-8, which belongs to the late pro-inflammatory factors, acting as a chemoattractant for neutrophils and promotes their recruitment to the site of inflammation [6]. An increase in IL-8 levels may be a sign of neutrophilic inflammation, although this cytokine is known to be synthesized by macrophages, lymphocytes, neutrophils, and other structural elements and can inhibit IgE production and histamine release [7]. However, it is most likely that the simultaneous maximum production of both IL-6 and IL-8 indicates a greater tension in the mechanisms of innate immunity (possibly due to the weakening of the mechanisms of acquired immunity due to senile immunodeficiency).
The system of pro-inflammatory cytokines in this work is represented by IL-4 and IL-10. It is well known that IL-4 is one of the main factors regulating the formation of IgE. The cytokine is synthesized by Th2-lymphocytes and other cells involved in the formation of allergic inflammation (mast cells, eosinophils, basophils). Its functions are mainly to activate and maintain the differentiation of T-helpers into Th2 cells and the migration of T-lymphocytes and eosinophils to the site of an allergic reaction [8]. Given that the study did not include patients with allergic rhinitis, it was noted that the level of detectable cytokine values was maximum in the group of the youngest patients with CRS and significantly exceeded that in patients aged 59-74 and 75-90 years. Considering that patients with allergic rhinitis were not included in the study, the results obtained probably indicate a lower anti-inflammatory activity of the immune system of age-related patients, possibly due to higher production of IL-10.
It is produced by Treg-lymphocytes, dendritic and other cells and is an anti-inflammatory cytokine with immunosuppressive activity [7]. Its activity is associated with both a suppressive effect on the mechanisms of acquired immunity and the ability to suppress the functional activity of macrophages and neutrophils [8].
Conclusions:
The maximum level of macrophage-monocytic cytokines (IL-6 and IL-8) and anti-inflammatory IL-10 is determined in the nasal wash in patients with CRS aged 75-90 years, the highest values of IL-4 detected are typical for patients aged 45-59 years.
About the authors
Natalya V. Tarasova
Volgograd State Medical University
Email: tarasova-nv@mail.ru
ORCID iD: 0000-0003-1929-5155
doctor of Medical Sciences, professor, head of the Department of Otorhinolaryngology.
Russian Federation, Volgograd State Medical University, Fallen Fighters Square, 1, Volgograd, Russia, 400066.Marya V. Sokolova
Volgograd Regional Clinical Hospital No. 1
Author for correspondence.
Email: mulia2585@yandex.ru
ORCID iD: 0009-0001-5503-2646
Postgraduate student of the Department of Otorhinolaryngology
Russian Federation, 400081, Russia, Volgograd, 13 Angarskaya StreetEleonora B. Belan
Volgograd State Medical University
Email: belan.eleonora@yandex.ru
ORCID iD: 0000-0003-2674-4289
doctor of Medical Sciences, professor, head of the Department of Allergology and Immunology.
Russian Federation, Fallen Fighters Square, 1, Volgograd, Russia, 400066.Аndrey V. Gorshenin
FSUE Research Institute of Hygiene, Toxicology and Occupational Pathology of the Federal Medical and Biological Agency of Russia
Email: angorshenin@yandex.ru
ORCID iD: 0000-0002-3272-4236
candidate of Medical Sciences, head of the Immunology Laboratory
Russian Federation, 400048,Russia,Volgograd, 12 Zemlyachki StreetReferences
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