Aims To identify an imbalance of cardiac remodeling mediators and monocytes subpopulation in blood, distribution of myocardium macrophages in patients with ischemic cardiomyopathy (ICMP). Methods The study engaged 30 patients with ICMP, 26 patients with coronary heart disease (CHD) without ICMP, 15 healthy donors. Concentrations of TGFβ, MMP-9, MCP-1, galectin-3 were measured in plasma of blood from the coronary sinus and peripheral blood in CHD patients, as well as in peripheral blood in healthy donors, by enzyme immunoassay method. The ration of classical, intermediate, non-classical, transitional monocytes in peripheral blood of patients and healthy donors was assessed by flow cytometry (expression CD14, CD16); the content of CD68+ macrophages in myocardium – by immunohistochemistry method. Results In both samples of blood, the content of galectin-3 in patients with ICMP was higher than in CHD patients without ICMP and the level of TGFβ was comparable between the groups. At ICMP, the concentration of MMP-9 in sinus blood was higher than that in CHD patients without ICMP in whom an excess of MCP-1 in the general blood flow was determined. The density of distribution of CD68+ cells in the myocardium in patients with ICMP was higher in the perianeurysmal zone than in the right atrium appendage. ICMP was characterized by a deficiency of non-classical monocytes, and CHD without ICMP – by an excess of intermediate cells in peripheral blood. Conclusion Myocardium remodeling at ICMP is mediated by not so much TGFβ but intracardiac galectin-3, which determines the subpopulation composition of blood monocytes.
Background: Monocytes and macrophages play an important role in atherogenesis and myocardial remodeling. Impaired differentiation of monocyte subpopulations may contribute to ischemic cardiomyopathy (ICMP). The aim of the present research was to study the features of the humoral cytokine-dependent regulation of differentiation of classical, intermediate, non-classical and transitional monocytes in bone marrow (BM) of CHD patients with or without ICMP. Materials and Methods: Forty-five patients with coronary heart disease (CHD), with and without ICMP (19 and 26 male patients, respectively), were examined. Subpopulations of classical (CD14 ++ CD16-), intermediate (CD14 ++ CD16 +), non-classical (CD14 + CD16 +), and transitional (CD14 + CD16-) monocytes in bone marrow (BM) samples were quantified by flow cytometry. Concentrations of IL-1β, IL-13, TNF-α, IFN-γ, and M-CSF in BM supernatants and blood plasma were evaluated by ELISA. Results: Concentrations of all cytokines in the blood and IL-1β, IL-13, TNF-α, М-CSF in BM supernatants as well as the capacity of М-CSF to activate, and IL-13 to inhibit, differentiation of classical monocytes from intermediate forms-were not dependent on the clinical form of CHD. Monocytopoiesis in ICMP was characterized by elevated BM concentration of IFN-γ, low М-CSF/IL-13 ratio, and a decreased percentage of classical and intermediate monocytes, accompanied by an increased number of transitional cells in BM, as compared to patients without ICMP. Conclusion: Excess of IFN-γ and low M-CSF/IL-13 ratio in BM were associated with inhibition of differentiation of mature monocyte forms and development of ICMP.
Aim. To evaluate the ratio of the fractions of classical, intermediate, non-classical and transitional monocytes in correlation with the concentration of interleukins 4 and 6 in the blood of patients with ischemic cardiomyopathy. Methods. 18 patients with ischemic cardiomyopathy (17 men and 1 woman) aged 47-66 years with circulatory insufficiency of functional class II-III according to the classification of heart failure of the New York Heart Association, were examined. The control group included 14 healthy donors matched by gender and age to patients with ischemic cardiomyopathy without any diseases of cardiovascular system and other systems in an exacerbation stage. In blood of the patients with ischemic cardiomyopathy, the relative content of classical (CD14++CD16-), intermediate (CD14++CD16+), non-classical (CD14+CD16+) and transitional (CD14+CD16-) monocytes was assessed by flow cytometry and the concentration of interleukins 4 and 6 by enzyme-linked immunosorbent assay (ELISA). Results. It was shown that the number of non-classical monocytes in the blood of patients with ischemic cardiomyopathy was 2 times lower than normal (5.05 % [4.08; 6.58] and 10.07 % [9.34; 13.84], respectively, p < 0.01), as well as the concentration of interleukin-4 (0.02 pg/ml [0; 0.04] and 0.15 pg/ml [0.05; 0.65], respectively, p < 0.05). The number of classical monocytes in the blood of patients had a tendency to decrease, and the proportion of intermediate monocytes and the concentration of interleukin-6, on the contrary, were slightly higher than in healthy individuals, and were interdependent (r = 0.61; p < 0.05). The relative content of transitional monocytes in the blood was comparable with that of healthy donors. Conclusions. The subpopulation composition of blood monocytes in patients with ischemic cardiomyopathy is characterized by a deficiency of the fraction of non-classical monocytes with protective properties against endothelium, and interleukin-4 in the blood with a certain increase in the content of interleukin-6 and the number of intermediate cells with ability to cooperate with T-lymphocytes, which predisposes to diffuse atheromatosis of small coronary arteries and diffuse hypoxic myocardial damage in ischemic cardiomyopathy.
The aim of the investigationwas to evaluate the ratio of classical (CD14++CD16-), intermediate (CD14++CD16+), nonclassical (CD14+CD16+) and transient (CD14+CD16–) monocytes in the blood and bone marrow in patients with chronic heart failure (CHF) against ischemic cardiomyopathy (ICMP).Materials and methods. 17 patients with ICMP and 14 practically healthy donors were observed. The material of the study was venous blood (in patients and healthy donors) and red bone marrow (in patients). In the materials the relative content of different monocytes subpopulations was determined by flow cytometry. The obtained results were analyzed by statistical methods.Results. It is shown that in the blood of patients the proportion of monocytes with the phenotype CD14++CD16- is 57.77 [of 46.35; 79.76]%, CD14++CD16+ – 25.06 [4.96; 42.31]%, CD14+CD16+ 5.05 [4.08; 6.58]% and CD14+CD16- – 6.03 [3.58; 10.89]%; in the bone marrow – 43.44 [40.54; 44.68]%, 0.16 [0; 1.07]%, 0,54 [0.35; 1.07]% and 54,32 [52.83; 56.08]%, respectively, which is different from the content of the data cells subpopulations in the blood (p < 0.05). At the same time, the content of non-classical monocytes in the patients’ blood is 2 times lower than in healthy donors, and the number of other cells varies within the norm.Conclusion. The differentiation of monocytes into 4 subpopulations in patients with CHF occurs directly in the bloodstream, since mainly the classical and transitional monocyte fractions with the prevalence of the latter are present in the bone marrow. Deficiency of non-classical monocytes of blood in CHF is probably associated with a disruption of their extramedullary differentiation.
<p><strong>Background.</strong> Chronic heart failure frequently occurs against the background of ischemic heart disease (IHD), and has also been associated with the diagnosis of ischemic cardiomyopathy (ICMP). While there are significant commonalities with respect to underlying mechanisms, it would be most important to identify differential diagnostic markers to facilitate diagnosis and verification at the early stages of disease.</p><p><strong>Aim.</strong> The intent of this study was to perform a quantitative assessment of non-classical monocytes in patients diagnosed with IHD with or without ICMP and to identify any relationships between non-classical monocytes and plasma concentrations of proinflammatory (interleukin (IL)-1β, IL-6, tumour necrosis factor (TNF)-α) and anti-inflammatory (IL-4, IL-10, IL-13) cytokines.</p><p><strong>Methods.</strong> We examined 44 patients diagnosed with IHD, aged 49 - 63 years, with class II-III heart failure as per the New York Heart Association criteria. Of this group, 18 were also diagnosed with ICMP. The comparison group included 14 age-matched healthy controls. Percentages of non-classical (CD14+CD16+) monocytes in peripheral blood were determined by flow cytometry and the concentrations of IL-1β, IL-4, IL-6, IL-10, IL-13 and TNF-α were measured by enzyme-linked immunosorbent assay.</p><p><strong>Results.</strong> Amongst the patients diagnosed with ICMP, the concentration of IL-10 in blood plasma was higher than in those without this diagnosis, detected at 30.05 pg/ml (range 24.75 - 33.50 pg/ml, р=0.0412); the percentage of non-classical monocytes was lower, at 5.05% (range 4.08 - 6.58%, р=0.0094). Amongst patients diagnosed with IHD without ICMP, these parameters were within normal limits. The plasma concentrations of IL-1β, IL-6 and IL-13 in both groups were comparable to values obtained from healthy donors and IL-4 was undetectable throughout. Amongst patients diagnosed with ICMP, plasma TNF-α was detected at elevated levels that were comparable to those determined for patients diagnosed with IHD without ICMP.</p><p><strong>Conclusion.</strong> Imbalance of cytokines in blood in patients with coronary artery disease is characterized by excess TNF-α, absence of IL-4, and normal levels of IL-1β, IL-6 and IL-13, regardless of the type of ischemic myocardial injury. In patients with ICMP, we detected an overall decrease in the fraction of non-classical monocytes in association with an increase in plasma IL-10; these features were not detected in patients diagnosed with IHD without ICMP. As such, these biological responses may be used for timely diagnosis of ICMP.</p><p>Received 27 May 2019. Revised 7 October 2019. Accepted 30 October 2019.</p><p><strong>Funding:</strong> The work is supported by grants of the Russian Foundation for Basic Research No. 18-015-00160\19 and the President of the Russian Federation No. НШ-2690.2018.7 and No. МД-2788.2019.7.</p><p><strong>Conflict of interest:</strong> Authors declare no conflict of interest.</p><p><strong>Author contributions</strong></p><p><strong></strong>Conception and study design: V.M. Shipulin, S.P. Chumakova</p><p>Data collection and analysis: V.M. Shipulin, S.P. Chumakova, O.I. Urazova, M.V. Vins, V.V. Novickiy</p><p>Literature review: S.P. Chumakova, D.A. Pogonchenkova, A.S. Pryakhin</p><p>Drafting the article: S.P. Chumakova, D.A. Pogonchenkova, O.I. Urazova</p><p>Critical revision of the article: V.M. Shipulin, V.V. Novickiy</p><p>Statistical analysis: S.P. Chumakova</p><p>Final approval of the version to be published: V.M. Shipulin, S.P. Chumakova, D.A. Pogonchenkova, O.I. Urazova, M.V. Vins, A.S. Pryakhin, V.V. Novickiy</p>
This literature review is devoted to the analysis of the role of macrophages in the immunopathogenesis of infectious lung diseases of bacterial etiology. The article summarizes information about the origin of macrophages, their phenotypic and functional heterogeneity. The mechanisms of impaired protective function of innate immunity are associated with the polarization of the program of maturation and activation of macrophages in the direction to tolerogenic or immunoregulatory cells with phenotype of M2. Alveolar macrophages perform a variety of functions (from pro-inflammatory to regenerative) in the development of inflammation in the respiratory organs. Their inherent plasticity suggests that the same macrophages can change their phenotype and function depending on the microenvironment in the inflammatory focus at different stages of the disease. Understanding the mechanisms that regulate macrophage plasticity will be an important step towards realizing the potential of personalized immunomodulatory therapy.
Цель исследования оценить соотношение фракций классических, промежуточных, неклассичес- ких и переходных моноцитов во взаимосвязи с концентрацией интерлейкинов (IL) 4 и 10 в крови у больных ишемической кардиомиопатией. Материал и методы. Обследованы 18 больных ишемической кардиомиопатией (17 мужчин и 1 женщина) в возрасте 4766 лет с недостаточностью кровообращения IIIII функционального класса по классификации сердечной недостаточности Нью-Йоркской ассоциации кардиологов. Группу контроля составили 14 практически здоровых доноров, сопоставимых по полу и возрасту с больными ишемической кардиомиопатией, не имеющих каких-либо заболеваний сердечно-сосудистой системы, а также других систем органов в стадии обострения. У больных ишемической кардиомиопатией в крови оценивали относительное содержание классических (CD14CD16), промежуточных (CD14CD16), неклассических (CD14CD16) и переходных (CD14CD16) моноцитов методом проточной цитометрии и концентрацию IL-4 и IL-10 методом иммуноферментного анализа. Результаты. Уровень неклассических моноцитов в крови у больных ишемической кардиомиопатией оказался существенно ниже нормы (5,05 4,08 6,58 и 10,07 9,34 13,84 соответственно, р0,008), как и концентрация IL-4 (0,02 0 0,04 пг/мл и 0,15 0,05 0,63 пг/мл соответственно, р0,039). Содержание IL-10 в крови было повышенным (30,05 24,75 33,50 пг/мл, р0,042) и негативно коррелировало с числом неклассических моноцитов (r0,65 p0,02). Количество классических моноцитов в крови у пациентов имело тенденцию к снижению, а доля промежуточных моноцитов, напротив, была несколько выше, чем у здоровых лиц. Относительное содержание переходных моноцитов в крови оказалось сопоставимым с показателями у здоровых доноров. Заключение. Субпопуляционный состав моноцитов крови у больных ишемической кардио- миопатией характеризуется дефицитом фракции неклассических моноцитов, обладающих протек- тивными свойствами в отношении эндотелия, и IL-4, при избытке IL-10 и некотором увеличении количества промежуточных клеток, обладающих способностью к кооперации с Т-лимфоцитами, что предрасполагает к распространенному атероматозу мелких коронарных артерий и диффузному гипоксическому поражению миокарда при ишемической кардиомиопатии.
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