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8у
(12,7%), на третьем месте - болезни органов пищеварения (8,3%), далее - болезни костно-мышечной системы (7,1%), глаза и его придаточного аппарата (6,7%), мочеполовой (6,5%), эндокринной системы (5,8%).
Курская область по общей заболеваемости взрослого населения отнесена к субъектам с низким уровнем заболеваемости, и в большей степени это относится к болезням системы кровообращения, так как в 2014 году по числу зарегистрированных случаев болезни системы кровообращения область была в группе субъектов РФ с самым низким показателем. Необходимо подчеркнуть, что в 2015 году общая заболеваемость в области стала повышаться, а болезни системы кровообращения стали регистрироваться на 17,4% больше (показатель заболеваемости увеличился с 12682 до 14887 на 100000 населения).
Проведённый анализ показывает, что соседствующие области: Воронежская и Курская - близки
и по медико-демографическим показателям и по заболеваемости. Поэтому так важно взаимодействие и руководства здравоохранением этих областей, и соседствующих медицинских вузов, чтобы в ходе решения задач приоритетного национального проекта лучше на местах аккумулировать накопленный опыт и направлять в Министерство здравоохранения России свои предложения по оптимизации работ, проводимых в рамках проекта. В свою очередь, Минздрав России, анализируя полученные отчетные материалы, разработает новые подходы, скорректирует планы в зависимости от реальной ситуации в субъектах Российской Федерации, расширит и изменит содержание работ.
В итоге сухая статистика уже положительной динамики достижения запланированных целевых показателей в реальной жизни выразится качественным изменением всей системы российского здравоохранения.
Литература:
1. Аналитический доклад «Итоги работы государственных медицинских организаций за 2015 год и первоочередные задачи на 2016»-Воронеж, 2016-221с
2. К вопросу об оказании паллиативной медицинской помощи на территории Воронежской области (на примере Верхнехавского района Воронежской области) Косолапов В.П., Чайкина Н.Н., Сыч Г.В., Васильева Г.В. В сборнике: Перспективы развития современной медицины Сборник научных трудов по итогам международной научно-практической конференции. 2015. С. 106-112.
3. Нагорная Е.В. Основные показатели медицинского обслуживания населения Курской обла-сти/Е.В. Нагорная// -МИАЦ.- Курск, 2015-59с
4. Распоряжение Правительства Российской Федерации от 11 ноября 2010 года №1950-р
5. Россия в цифрах, 2016 С.157-158 [Электронный ресурс] http://www.gks.ru/free_doc/doc_2016/rusfig/rus16.rar (дата обращения: 02.09.2016).
6. Хальфин Р..А. Приоритетный национальный проект в сфере здравоохранения: результаты и перспективы /Р..А. Хальфин // Экономика здравоохранения №11 - доклад от 16.02.2007 на Всероссийском совещании руководителей органов управления здравоохранением субъектов РФ и исполнительных директоров территориальных фондов ОМС-М.
UDC 612.112.94+616.233-002+616.12-009.72
Herych R., Yatsyshyn R.I.
SHEE «Ivano-Frankivsk national medical university»
STATE OF LYMPHOCYTE ACTIVATION REACTIONS IN PATIENTS WITH COPD ASSOCIATED WITH STABLE ISCHEMIC HEART DISEASE
Abstract. With the aim of determining the capacity of immune cells (mononuclears) for activation we performed phenotyping of activation markers, which were evaluated against the following parameters: CD25+ marker of activated Т- and В-lymphocytes and monocytes, CD95+(Fas/APO-I) - antigen, which is expressed by the membranes of activated mononuclears and points to their apoptosis, IP047+(HLA-DR) - main histocompatibility antigen of class II lymphocytes and CD150+(in03+) - marker of thymocytes and activated lymphocytes.
The study involved 60 patients with chronic obstructive pulmonary disease (COPD) stage III, groups С and D in the exacerbation phase, which underwent inpatient treatment. The main group (n=33) involved patients with isolated course of COPD, and experimental group comprised patients (n=27) with COPD complicated by comorbide stable ischemic heart disease (SIHD), stable effort angina (SEA) of FCI-II. Control group involved 18 apparently healthy individuals (AHI). The detected changes of subpopulations and activation reactions of peripheral blood lymphocytes in patients with COPD exacerbation stage III in both patients with isolated course and in combination with SIHD, indicate disorders in the process of lymphocytic cooperation in immune response, as well as between processes of positive and negative activation. It may be assumed that, multi-vector nature and multidirectionality of changes in cellular component of immune system in COPD patients with SIHD are in close association with the variability of clinical manifestations.
Key words: systemic cardiovascular effects, immunocompetent cells, lymphocytes.
COPD and cardiovascular diseases are often common risk factors [2, 26, 36]. The rate of such combined, which is primarily due to the presence of combination makes more than 50% within disease
incidence among aged population. It is observed that practically all forms of systemic cardiovascular effects (SCE) (SIHD, arterial hypertension (AH), arrhythmias) are registered in COPD patients. The causes of SCE in COPD patients are: inflammatory activity of pulmonary tissue cells because of chronic systemic inflammation, perfusion-ventilation hypoxemia and tissue hypoxia, impact of dyspnea on metabolism, as well as smoking, industrial pollutants, genetic factors [25]. At the present time COPD is considered as chronic non-allergic persistent inflammation of bronchi, lung parenchyma and vessels with systemic aftereffects [31]. Hospitalization rate of COPD patients for cardiovascular diseases is higher than for exacerbation of COPD itself [2, 25, 26, 35]. In recent years scientists discovered the role of inflammation and leukocyt-ic activation in the development of acute coronary syndromes as the cause of more significant myocardial damage [1, 2, 3, 15, 17, 32].
Today in addition to determining the number of main subpopulations of lymphocytes in peripheral blood, concentration of main classes of immunoglobu-lins in blood serum and functional activity of phagocytes, significant attention is paid to the study of immune cells' capacity for activation, proliferation, differentiation (effector function) and regulation [18, 20, 21, 27]. After activation, immunocompetent cells (ICC) undergo typical process of their development -they start to proliferate and then are differentiated into mature cells that finally provide effector functions (secretion of cytokines, cytotoxicity, etc.) of the immune system (positive process). That is why while evaluating the ICC state one should determine the type of activation - positive or negative.
According to Chernyi V.I. and Nesterenko A.N. [22], the same stimulus that is aimed at the same population of cells but completed in conditions which differ from the previous or under conditions of factor deficiency that provide proliferation, may lead to adverse effect - apoptosis of activated cells (negative process). CD95+(Fas/APO-I) marker is expressed by the membranes of activated mononuclears and is used as one of the apoptotic markers allowing to evaluate the degree of negative ICC activation [8, 13, 15, 24]. These processes are the most significant for T-cells.
Belotskyi S.M., Avtalio R.R. [5] proved that the cooperation of "receptor-ligand": Fas/Fas-L plays critical role in negative type of mature T-cells activation. Activated T-cells are expressed as Fas, as well as its ligand Fas-L and become sensitive to cell death, which is the result of binding of Fas-receptor for Fas-L - ligand [5]. Decrease in the number of lymphocytes with CD95+ markers leads to the accumulation of pool of self-reactive lymphocytes that may result in autoimmune reactions [5, 10, 30].
Identification of typical antigenic systems of the major histocompatibility complex (МНС) is responsible for the regulation of immune response at its various stages. МНС is a large group of genes (in humans it is called the HLA - Human leukocyte antigens) comprising classes I, II and III with different genetic loci. The HLA system includes three components: abbreviation of the entire system; locus that contain
this specificity (A, B, C, DR, DQ, etc.); antigen number (e.g., HLA-DR-3).
According to present-day data, the HLA system assures regulation of immune response and performs such following important physiological functions as: interaction of all the ICC of the body, discrimination of self from non-self, including transformed cells, and in general, insures human survival in conditions of exogenous and endogenous aggression [19, 20, 27]. MHC genes are responsible for genetic control of immune response quality (prof. Drannik H.M.).
Diagnostic significance. The increase of count of cells with CD95+ - receptors may both indicate immune system activation (CD95+ - marker of late activation of immune response along with HLA-DR+ -antigen), and be the marker of readiness to apoptosis, which is triggered by the interaction of Fas/Fas-L. CD95+ - receptor is mainly differentiated on T-cells, particularly on T-helpers. While CD95+L - receptor is more often found on T-killers. The increase of apopto-sis marker is characteristic of vital infection, chronic course of inflammatory process [13]. Identification of decreased expression of (HLA-DR+) - antigens on lymphocytes is pathognomonic for the prognosis of further development of systemic inflammation response syndrome and correlates to the secretion of pro-inflammatory cytokines, including IL-8, and may be the indicator of immune paralysis (Chernyi V.I., Nesterenko A.N.).
The purpose of our investigation was to study the activation processes of regulatory T- and B-cells of peripheral blood in patients with exacerbation of COPD stage III, groups C and D in both isolated course of the disease and in combination with SIHD, SEA of FC I-II and compare them with the indices of apparently healthy individuals (AHI).
Object and methods of investigation. The study involved 60 patients with exacerbation of COPD, who received in-patient treatment at the Allergology Unit of the Regional Clinical Hospital and at the Diagnostic Department of the Regional Phthysio-pulmonary Centre. The age range of patients was from 40 to 77 years (the average age was 59.0±14.3 years). There were 47 (78.33%) male and 13 (21.63%) female patients.
The COPD diagnosis was verified according to the stages of disease according to the order of the Ministry of Health Care of Ukraine №555 from June 27, 2013 "On approval and introduction of medical and technological documents for standardization of medical care in chronic obstructive pulmonary disease" and regulations set out in the GOLD document [31]. In the course of this study SIHD and SEA of FC I-II were qualified as comorbide states of COPD, while comorbidity itself was defined as the presence of one or more effects (after-effects, manifestations), which are pathogenetically caused by COPD [11].
All the examined patients were divided into two groups, represented according to their age, sex and disease severity. The main clinical group involved 33 (55.0%) patients with isolated course of COPD stage III; and the experimental group comprised 27 (45.0%) patients with COPD stage III complicated by comor-
y
bide stable ischemic heart disease (SIHD). Patients were diagnosed with SIHD either during their previous in-patient course of treatment at the therapeutic and cardiological stations or during out-patient treatment and confirmed by us in the course of dynamic clinical, laboratory and instrumental examination.
Phenotyping of T- and B-lymphocytes, T-helpers/inductors, T-suppressors/cytotoxic cells (CD3+, CD4+, CD8+, CD16+, CD22+) was conducted by identifying differentiated antigens with the help of immunofluorescence test using monoclonal antibodies produced by CJSC "Sorbent-Servis" (Moscow, Russia), which belong to clusters of differentiation. The specimens were studied under luminescence microscope, complete with phase-contrast device ("Li-umam-I3") [8]. With the aim of evaluating the capacity of immune cells (mononuclears) for activation we carried out phenotyping of activation markers, which were assessed according to the following parameters: (CD25+) - activated T- and B-lymphocytes and monocytes (CD150+(in03+) - activated lymphocytes, CD95+ - markers of apoptosis, IP047+(HLA-DR+) -class II lymphocyte antigen by means of standard methods [20].
The obtained data were processed by means of variation statistics method using computer software Excel 7.0 and Statistica for Windows. The differences between samples were considered reliable at p<0.05.
Results and their discussion. We investigated the phenotype peculiarities of peripheral blood leukocytes in patients of the main and experimental groups. The results of immune status study before treatment are given in Table 1. As Table 1 shows, considerable changes in the cellular component of immune system were noticed in patients with exacerbation of COPD stage III as compared to apparently healthy individuals: namely, the percentage and absolute lymphocyte count of CD3+ and CD4+ cells was considerably reduced associated with the decrease of absolute number and percentage of CD16+ cells (p<0.05). It is thought to be the result of the development of secondary immunodeficiency and caused by toxic effect of pathogenic microflora and redistribution of antigen-reactive cells and their accumulation in the focus of inflammation [6, 14, 18]. It is known that the function of CD4+ T-cells is to recognize the antigen, produce lymphokines and thus triggering and regulation of all T-cell-dependent immune reactions [10, 14, 15, 18]. That's exactly why their deficiency in isolated course of COPD and in combination with SIHD is the signif-
icant evidence of incoordination of immune system functioning in this cohort of patients.
The CD8+ index of peripheral blood lymphocytes at the time of initial examination increased to 1.22 times (p<0.05) in patients with isolated course of exacerbated COPD stage III and 1.43 times (p<0.05) in COPD patients complicated by SCE. This increase of relative and absolute content of cytotoxic T-suppressors may point to predisposition to chroniza-tion of inflammatory process in bronchopulmonary complex and prolonged course of disease. Consequently, the correlation of CD4/CD8 (immunoregula-tory index) was decreased in patients of both groups. The obtained findings are consistent with the results of our previous studies [7] and data provided by other scientists, who confirm the increase of CD8+ T-cell count also in bioptic samples of bronchial mucosa in COPD patients [4]. We believe that discovered changes of CD4+ and CD8+ in peripheral blood lymphocytes in patients with COPD exacerbation are prominent evidence of disorders of the lymphocytic cooperation processes in immune response [7].
Immunoregulatory index was extremely low in the group of patients suffering from COPD with SIHD due to the increase of CD8+ cells (cytotoxic suppressors) that indicates disbalance of immunoregulatory subpopulations of T-lymphocytes and may be the reason for the conclusion that disbalance in immune system is one of the pathogenetic mechanisms of this combination (COPD and SIHD). Preliminary studies point out that activation of T-cell cytokine cascade itself considerably predetermines the production of organ-specific autoantibodies and is the direct inductor of hypersensitivity disease and cardiomyopathy development [2, 14, 17, 32].
We have also noticed the deficiency of NK-cells (CD16+) in COPD patients stages II and III in both groups as compared to the control group (16.9±0.61)% at the course of primary immunological research. It is known that NK-cells carry out important regulation of inflammatory process and are main defenders of the body against microbes at the stage of acute immunologic response [16]. Deficiency of NK-cells leads to the development of acute respiratory infections and chronization of infectious-inflammatory processes of varied localization [22]. Our records indicate that more prominent deficiency of natural killer cells correlated to the severity of disease, especially in patients with COPD combined with SIHD. The obtained findings coincide with the study results of other scientists [7, 16, 23].
Table 1
Quantity characteristic of cellular component of immune system (leukocytes, lymphocytes, their subpopulations and proliferative activity) in patients with isolated course of COPD exacerbation and in combination with SIHD
Indices Control group AHI (n=18) Main group (n=33) Experimental group (n=27)
CD3+ (Т-lymphocytes), х109 2.22±0.14 2.18±0.13 2.09±0.19
g/l, % 68.45±3.87 67.65±3.24 64.44±3.11
CD4+ (Т-helpers), 0.85±0.04 0.84±0.04 0.74±0.03
х109 g/l, % 26.18±2.03 25.7±1.03 22.8±1.89
CD8+ (Т-suppressors), х109 0.52±0.03 0.63±0.04 0.69±0.05
g/l, % 22.44±1.03 27.47±1.14* 32.12±2.08*
CD16+ (NK), 0.46±0.05 0.37±0.04 0.33±0.03
х109 g/l, % 16.9±0.61 13.6±0.54* 12.2±0.51*
CD4+/CD8+ (IPI) 1.63±0.19 1.33±0.16 1.07±0.09
CD56+(NK), % 18.31±1.18 14.81±1.21* 12.86±1.24*
CD25+ 0.270±0.26 0.298±0.29 0.339±0.31
(activated Т- and В- 13.85±0.49 15.3±0.44 17.43±0.24
lymphocytes), x109g/l, %
CD150+(IP03+), % 8.62±0.72 5.54±0.35* 4.78±0.32*
CD95+(Fas, APO-I), 0.83±0.014 1.82±0.018* 2.05±0.019*
х109 g/l, % 7.62±0.72 12.16±0.58* 18.12±0.84*Л
Note: * - p<0.05 between group and control, A - p<0.05 as compared between groups.
We have investigated the cell count in the state of apoptosis in blood of patients with COPD (табл. 1). The study revealed increase of expression of CD95+ (Fas/APO-I - marker of apoptosis on peripheral blood lymphocytes) by 1.6 times (p<0.05) in patients of the main study group and by 1.82 times (р<0.05) in patients of the experimental group as compared to the control indices - (7.62±0.72)%. The highest concentrations of CD95+ (Fas/APO-I) - lymphocytes are noticed in COPD patients with SIHD (18.12±1.12)%, (р<0.05). The obtained findings indicate the presence of excessive or chronic antigenic stimulation in the exacerbation phase of the disease that promotes activation of lymphocytes and increases their readiness to Fas-dependent apoptosis, as well as the development of systemic after-effects. On the other side, increase of CD95+ antigen expression, which generates apoptosis, shows elimination of these cells that may lead to the development of latent immune deficiency in COPD complicated by SCE. It is also known that maintenance of control over the balance of acceleration and suppression of apoptotic IKC death may interfere with the main problem of COPD - chronization of inflammation and, as a result, lead to progressive disease [6, 13, 28]. Agnoletti L. et al. (1998), (Avdeiev S.N.) discovered the increase in expression of (Fas/APO-I) -
receptors on the lymphocytes in patients with chronic heart failure (CHF) that is associated with the increase of their apoptotic index. It has been established that apoptotic index in myocardial cells in patients with CHF was considerably higher than in interstitial cells, and the degree of apoptotic changes correlates well with the severity of myocardial dysfunction. At the same time, the increase of "programmed death cell" count may show not only proliferation, but also the inability to trigger the cell death program under the influence of factors which cause apoptosis in the norm [10, 21].
We have studied the correlation relationship of (Fas/APO-I) - receptors on lymphocytes with other antigens of lymphocytes. The analysis of expression correlation in CD95+ (Fas/APO-I) and other markers of lymphocytes indicates the correlation of changes in the content of CD95+ and CD8+, CD95+ and CD25+ lymphocytes (r= 0.38 vs r=0.40), (p<0.05).
The comparative analysis of activation of IP047 (HLA-DR+) - lymphocytes showed their considerable increase in the experimental group of patients, while the difference between average-group indices turned out to be inaccurate in patients from opposed groups (p>0.05) (Table 2).
Table 2
Comparative characteristics of IP047+ (HLA-DR+) lymphocytes __in patients with COPD stage III__
Indices, % Control group, (n=18) Main group, (n=33) Experimental group, (n=27)
IP047+(HLA-DR+) lymphocytes 11.18±0.87 15.08±1.12* 17.23±1.28*
Note: * p<0.05 between group and control.
The comparative analysis of IP047+(HLA-DR+) - lymphocyte activation showed distinct changes on the part of their quantitative content in the peripheral
blood. Thus, the level of IP047+(HLA-DR+) cells was increased by 1.35 times (p<0.05) to (15.08±1.22)% in patients with isolated course of
y
COPD as compared to the indices in the control group (11.18±0.87)%, while in patients with COPD combined with SCE it increased by 1.54 times (p<0.05). At the same time, while analyzing the results of our research work (Table 2) it became possible to identify considerable decrease by 1.32 times (p<0.05) of CD150+ (in03+) in subpopulations of thymocytes and activated lymphocytes in peripheral blood of patients with isolated course of COPD in the phase of exacerbation as compared to the group of apparently healthy individuals, that is obviously explained by their delivery to bronchus-associated lymphoid tissue with the aim of further participation in humoral reactions of immunoglobulin synthesis. We have not established any significant changes of B-lymphocytes and granulocytes CD24+(IP024+) in peripheral blood of patients from both study groups as compared to the control group.
The research findings of Lykov V.F. [15] show that the development of SCE is accompanied by the increase of CD24+, CD 16+, CD25+ lymphocyte count, considerable increase in the number of cells with CD95+ phenotype and tendency to the increase in CD50+ lymphocytes. AS reported by other scientists, ischemia and chronic inflammatory process in IHD may trigger not only apoptosis of cardiomyocytes but also modulate the number and activity of lymphocytes and neutrophils [17, 34]. Changes in the ICC phenotype influence the development of cardiovascular pathology, consequently the effectiveness of SCE therapy must be based on the study of specific patterns of these changes. Many scientists are of the opinion that inflammatory reaction and expression of activation processes occur in the myocardium regardless of the reason for heart failure [14, 15, 17, 32]. Hypoxemia is one of the leading damaging factors of myocardium in COPD patients, because it causes hy-poxic myocardiodystrophy of both right and left ventricles with the development of CHF [1, 3, 25]. The number of pro-inflammatory cytokines, including TNF-a, IL-1a, IL-ip, IL-6, was increased in the blood plasma of patients with CHF regardless of its etiology [2, 17, 32].
The discovered changes in lymphocyte pheno-types (increase in the expression of adhesion molecules, activation antigens) associated with the development of chronic heart failure may be explained by the increase of pro-inflammatory cytokine concentra-
tion [2, 17, 29]. Pathophysiological activity of proinflammatory cytokines is aimed at fever induction, synthesis of acute-phase proteins, initial activation and proliferation of T-helper cells, positive chemotaxis of neutrophils and mononuclears into the affected area, limitation of the inflammatory process by strengthening of surface pro-coagulative activity of endothelial cells and reducing the expression of tissue-type plas-minogen activator that enables the formation of protective fibrinous barrier [2, 17, 32].
Such focused attention to the study of immunity in COPD with SIHD, especially in the presence of cardiovascular effects, is associated with the fact that neurohumoral pattern of CHF development cannot always explain the causes and mechanisms of formation and progression of left-ventricular dysfunction (Chuchalyn A.H.). Currently a new theory of CHF progression was suggested. It is based on the data about immune activation and systemic inflammation as a marker of poor prognosis and high cardiovascular risk (Bachetti et al.; Taubert G. et al.). This concept states that non-specific activation of macrophages and monocytes in plasma and intercellular fluid, which is realized in severe disorders of microcirculation, is the inductor of synthesis of pro-inflammatory cytokines, which identify left-ventricular dysfunction. However, the role of systemic inflammatory response in hemo-circulatory disorders, as well as in the formation of endocardial and myocardial dysfunction still remains unclear. Researches, who study this problem, pay much attention to the pro- and anti-inflammatory cytokines, chemokines, adhesion molecules, soluble receptors of apoptosis and growth factors [2, 17, 32].
Conclusion. The study of indices characterizing cellular, humoral and autoimmune components of protective response showed their considerable alteration in COPD and according to the stage of disease, degree of exacerbation and presence of SIHD indicated the presence of secondary immune deficiency in patients.
We believe that the detected changes of subpopulations and activation reactions of peripheral blood lymphocytes in patients with COPD exacerbation stage III in both patients with isolated course and in combination with SIHD, indicate disorders in the process of lymphocytic cooperation in immune response, as well as between processes of positive and negative activation.
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