Clinical significance of endothelial dysfunction in children with recurrent obstructive bronchitis and bronchial asthma

Bronchial asthma (BA) is one of the most common childhood diseases. Epidemiological studies of recent years indicate that 5 to 10% of children suffer from this disease, and this figure increases every year. The increase in mortality from bronchial asthma and the number of hospitalizations in pediatric institutions is also of serious concern. In recent years, endothelial dysfunction has been of great interest to researchers studying the mechanisms of bronchial asthma development. The endothelium is a metabolically active, highly specialized monolayer of cells lining all vessels of the human body. Endothelial cells, specifically responding to various molecular signals, perform a variety of functions, including transport, barrier, participate in the metabolism of the extracellular matrix, biosynthesis of various cytokines, angiogenesis, regulate blood clotting processes, vascular tone and immune-inflammatory reactions, participate in the production and metabolism of nitric oxide. The endothelium participates in the regulation of systemic and pulmonary vascular tone by forming and releasing vasodilator and vasoconstrictor substances, in particular endothelin-1 and endothelium-dependent relaxing factor - nitric oxide (NO). Dysfunction of the endothelium, occurring under the influence of damaging agents (mechanical, infectious, metabolic, immune complex, etc.), sharply changes the direction of its endocrine activity to the opposite: vasoconstrictors, endothelins, coagulants are formed. Dysfunction of the endothelium disrupts the ratio between NO (antiplatelet agent, anticoagulant, vasodilator) and peroxynitrate - a metabolite of NO, which increases the level of oxidative stress, which leads to various pathophysiological reactions. In the last decade, researchers have emphasized the damaging effect of proinflammatory cytokines (IL-1-β, TNF-a, IL-8, etc.) on the vascular endothelium, triggering a cascade of processes from local vasoconstriction and release of growth factors to vascular wall remodeling processes. In this regard, the issue of the relationship between immune-inflammatory activation and the state of the vascular endothelium in patients with bronchial asthma is of particular interest. Endothelial dysfunction is considered as one of the possible pathogenetic mechanisms for the development of bronchial asthma. Morphologically, patients with bronchial asthma have an increase in the cross-section of the submucosal layer of blood vessels, an increase in the number of vessels in the walls of the respiratory tract, and thickening of the intima. Similar elements of remodeling are detected already in childhood against the background of a mild course of bronchial asthma.

The mechanisms of endothelial dysfunction and vascular remodeling in the respiratory tract are still poorly understood, which served as a prerequisite for our study.

The aim of the work was to study the function of the endothelium in children with recurrent obstructive bronchitis and bronchial asthma in the period of exacerbation and remission.

A total of 147 sick children aged 1-17 years were examined. According to the nosological forms and severity of the disease, the children were divided into groups: patients with recurrent obstructive bronchitis (group 1), intermittent bronchial asthma (group 2), persistent bronchial asthma of mild degree (group 3), persistent bronchial asthma of moderate or severe severity (group 4) during an exacerbation of the disease (respectively subgroups 1A, 2A, 3A, 4A) and in the period of remission (respectively subgroups 1B, 2B, 3B, 4B).

The level of endothelin-1 (ET-1) in the blood was determined by the enzyme immunoassay method using standard reagents from DRG (USA). NO in the blood was determined by the level of final metabolites (nitrites (NO2) / nitrates (NO3)) by the calorimetric method using Griess reagents. Doppler echocardiography of the heart and blood vessels was performed on the AU 3 Partner ultrasound device from Esaote Biomedica (Italy) with measurement of the average pressure in the pulmonary artery according to Kitobataka. The control group included 13 practically healthy children of the same age without signs of any acute or chronic diseases.

Statistical analysis of the data was performed using the statistical packages Excel lor Windows and Statistica 7.0. For Windows.

Given the lack of data on the significance of the levels of the indicators selected for the study in healthy children, children in the control group were examined to determine the normative parameters.

The period of exacerbation of bronchial asthma and recurrent obstructive bronchitis was characterized by pulmonary ventilation disorders of varying severity. As is known, ventilation disorders lead to the development of alveolar hypoxia, which cannot but affect the state of endothelial function.

When assessing the parameters during the exacerbation period, the level of the vasoconstrictor factor ET-1 increased significantly in all groups and was highest in the group of children with severe and moderate bronchial asthma (subgroup 4A). The course of the disease in subgroup 4A was characterized by pronounced ventilation disorders of the obstructive type, leading to alveolar hypoxia, which is a powerful inducer of ET-1. In addition to the inducing role of hypoxia, this group of patients is characterized by pronounced immunopathological reactions both in intensity and in duration of the course, which also contribute to a greater release of ET-1 by the vascular endothelium.

The conducted analysis of multiple comparisons by the Kruskal-Wallis method revealed a highly significant criterion H (H = 38.02, p = 0.0001), which gives the right to assert that the statistical characteristics of ET-1 levels in patients of different subgroups during the exacerbation period differ significantly from each other, and their level depends on the patient's belonging to a particular subgroup. Since patients were divided into groups according to the severity of the disease, we can talk about the presence of a relationship between the level of ET-1 and the severity of the disease.

Thus, in subgroup 1A, endothelial dysfunction was characterized by a moderate increase in ET-1 levels and a decrease in nitrate and nitrite levels in the blood. In patients in subgroups 2A and 3A (mild bronchial asthma), against the background of a moderate increase in ET-1 levels (0.1-0.13 ng/ml), there was a reliable decrease in nitrite levels (4.44-4.64 μmol/l) compared to the control and equalization of NO metabolism indicators due to a relative increase in nitrate levels (31.54-33.48 μmol/l). This imbalance can be considered prognostically unfavorable due to the fact that an increase in nitrate levels is associated with increased lipid peroxidation, highly active free radicals and an increase in the activity of inducible NO synthase (iNOS) in vascular smooth muscles and macrophages. In patients in subgroup 4A with severe bronchial asthma, the imbalance was even more pronounced: against the background of a high level of ET-1 (up to 0.2 ng/ml), a more pronounced inhibition of endothelial NO synthase (eNOS) was noted, which was manifested by a decrease in the level of nitrites (6.19 μmol/l) and pronounced activation of iNOS, which resulted in an increase in the level of nitrates and total NO metabolites compared to the control group.

To determine the presence of a functional relationship between the ET-1 level and the indicators characterizing the course of chronic obstructive pulmonary diseases, a multiple linear regression procedure with stepwise exclusion of insignificant variables was used. As a result of the analysis, a mathematical model was obtained:

ET-1 = -0.00368+(0.0142 x disease duration) + (0.00532 x PLA), with R = 0.672; R2 = 0.525; dbf = 2; F = 8.408; p = 0.001.

The multiple regression coefficient R reflects the presence of a statistically significant relationship between the ET-1 level and independent variables (disease duration), as well as the mean pulmonary artery pressure (PLA). At the same time, the determination coefficient R2 makes it possible to state that the increase in the ET-1 level by 52.5% is due to a change in the level of independent variables of this equation, namely, the disease duration (p = 0.008) and PLA (p = 0.022).

Assessing NO metabolism by its final metabolites (nitrites, nitrates) in children in subgroups, it can be noted that it changed in different directions. In patients of subgroup 1A with exacerbation of recurrent obstructive bronchitis, a decrease in the level of NO metabolites - both nitrites and nitrates - was noted, which indicated a deficiency of NO-dependent endothelial function, with the most pronounced decrease in the nitrite level. At the present stage, the blood nitrite level is regarded as a predictor of endothelial eNOS activity. This indicates a pronounced inhibition of eNO synthetase, a weak iNO response.

During the remission period, the ET-1 level in all groups remained moderately elevated in the range of 0.05-0.15 ng/ml compared to the control group and was most elevated in subgroup 4B to 0.15 ng/ml. Such ET-1 levels indicate that subgroup 4B, compared to other subgroups, retains the highest metabolism of vasoconstrictor factors (ET-1) in the vascular endothelium. This may be due to the fact that patients with severe bronchial asthma retain latent obstructive changes in the function of external respiration, alveolar hypoxia, which stimulates the highest release of ET-1 by endothelial cells.

The highly significant Kruskal-Wallis criterion H (H = 34.68, ^ = 0.0001), established as a result of multiple comparison, gives the right to assert that the statistical characteristics of the ET-1 indicators of different subgroups differ significantly from each other, and their level depends on the patient's belonging to one or another group. Thus, as in the period of exacerbation, we can talk about the presence of a connection between the level of ET-1 and the severity of the disease.

An additional analysis of the correlation between the level of ET-1 and the indicators of the course of chronic obstructive pulmonary diseases revealed the presence of a reliable direct relationship between the level of ET-1 and PLA (r = +0.38, p < 0.014) in patients in the period of remission.

NO metabolism in the studied groups behaves differently. In the group of children with recurrent obstructive bronchitis (subgroup 1B), an increase in the blood nitrite level to 5.48 μmol/l is noted, although they remain reduced compared to the control group, and a marked increase in the nitrate level to 41.45 μmol/l, which can be regarded as a compensatory response to endothelial NO deficiency. In groups of children with mild bronchial asthma, a moderate increase in nitrites to 5.6-6.45 μmol/l (which is lower than in the control group) was noted. This can be regarded as an increase in eNOS activity and the protective effect of NO metabolites. The most pronounced imbalance in NO metabolism was noted in children of subgroup 4B, which manifested itself in a decrease in the nitrite level compared to the exacerbation phase and an increase in the nitrate level. These data may indicate a pronounced suppression of eNOS even during remission and persistent pathological activity of iNOS.

As a result of the conducted research, the following conclusions can be drawn.

In children with recurrent obstructive bronchitis and bronchial asthma, changes in the levels of endothelium-dependent factors (ET-1 and NO metabolites) were detected depending on the stage and severity of the disease.

In the acute phase of the disease, patients of all subgroups showed unidirectional changes in the form of an increase in the level of ET-1, with the most pronounced changes in patients with severe and moderate bronchial asthma up to a level of 0.2 ng/ml.

The existence of a functional relationship between the level of ET-1 and indicators characterizing the course of chronic obstructive pulmonary disease (duration of the disease) and the level of average pressure in the pulmonary artery in patients with recurrent obstructive bronchitis and bronchial asthma during an exacerbation of the disease has been proven.

Changes in the levels of NO metabolites (nitrates, nitrites) were multidirectional in nature, in the form of a persistent decrease in nitrites in the exacerbation and remission phases and an increase in the level of nitrates mainly in severe bronchial asthma.

In patients with recurrent obstructive bronchitis and bronchial asthma, the presence of endothelial dysfunction was revealed, and more pronounced in patients in the acute stage, which was manifested in the form of vasoconstriction, an increase in the average PLA and the level of ET-1, the synthesis of which was induced by hypoxia and pathoimmunological reactions. At the same time, a low level of the NO metabolite (nitrite) is associated with the inhibition of endothelial NO synthetase, and an increase in the nitrate level is associated with the production of pathogenic NO (inducible NO), which could serve as a factor leading to the destruction of the endothelium and the maintenance of the pathological process in the lungs.

V. V. Polyakov, Prof. A. S. Senatorova. Clinical significance of endothelial dysfunction in children with recurrent obstructive bronchitis and bronchial asthma // International Medical Journal No. 4 2012

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