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^ЛГ/ребёнка
КёУчна пед1атр1я / Clinical Pediatrics
UDC 616.2-022.1-036.11:[616.1-072.7]-053.9 DOI: 10.22141/2224-0551.14.4.2019.174032
L.S. Ovcharenko, D.M. Sheludko, A.O. Vertehel, I.V. Samokhin, T.G. Andrienko, A.V. Kryazhev State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine", Zaporizhzhia, Ukraine
Neurotransmitter serum levels in children with recurrent upper respiratory tract infections
For citation: Zdorov'e Rebenka. 2019;14(4):205-210. doi: 10.22141/2224-0551.14.4.2019.174032
Abstract. Background. Schoolchildren are prone to frequent respiratory tract diseases. In the structure of general morbidity, this pathology ranks first. Its prevalence is more than 60 %, which leads to frequent school absenteeism, lack of active games and outdoor walks. So, there is an increase in the amount of time that a child spent on means of mass electronic communication and electronic games, resulting in high affection and addiction, forming hypodynamia, which in aggregate has a negative impact on the regulatory systems functioning. Recurrent upper respiratory tract infections (URTI) contribute to the strain of neuro-endocrine-immune regulation, causing an imbalance of neuropeptides — mediators of neurogenic inflammation. The purpose of this work is to study the neurogenic inflammation parameters in schoolchildren with functional disorders of the cardiovascular system and recurrent respiratory tract diseases. Materials and methods. We surveyed 130 children with URTI aged 6 to 9 years in the somatic well-being period. The analysis of the contents of vasoactive intestinal peptide (VIP), substance P andfinal stable metabolites of nitric oxide (FSM NO) in serum was carried out. An increase in substance P level in children with recurrent URTI was found, which had statistically significant differences with the healthy children indices (p < 0.05). Results. It has been found that high concentration of substance P increases the risk of recurrent URTI. It has been proved that in children with recurrent URTI due to increased FSM NO serum content that has a pro-inflammatory orientation, there is an increased neurogenic inflammation activity. It was found that the reliable reduction in the content of VIP as an anti-inflammatory transmitter in children with recurrent URTI can not suppress the activity of neurogenic inflammation, resulting in its excessive stimulation. Conclusions. Children with recurrent URTI in the somatic well-being period have increased serum levels of substance Р and FSM NO. In the somatic well-being period in schoolchildren with recurrent URTI, a decrease in the concentration of antiinflammatory neuropeptide VIP is observed.
Keywords: children; neuropeptides; substance Р; recurrent upper respiratory tract infections
Introduction
The human nervous and endocrine systems are controlled by adaptive homeostasis functioning. The nervous system influence is realized in the tissues through cell cho-linergic and adrenergic receptors by altering the activity of the endocrine glands, as well as by the formation of active protein molecules — neuropeptides [8]. It is known that the inflammatory reaction pathogenesis goes beyond the immune mechanisms and involves neuronal interactions. This is due to the ability of immune cells stimulated by inflammation to produce neuropeptides similar to those produced
in the central nervous system [11]. Neuroendocrine cells of the brain and immune cells are in close co-operation and exhibit signs of similarity in their organization [3, 8].
Among neuropeptides, we can identify those with antiinflammatory (vasointestinal peptide (VIP)) and proinflammatory (substance P) effects [1, 5, 6]. VIP is produced by neurons, endocrine and immune cells and is present in most organs, including the central nervous system, heart, lungs, thyroid gland, kidneys, urinary and gastrointestinal tract, genital organs and immune system [2, 7]. VIP suppresses the expression of other inflammatory mediators [5]. Recent
© 2019. The Authors. This is an open access article under the terms of the Creative Commons Attribution 4.0 International License, CC BY, which allows others to freely distribute the published article, with the obligatory reference to the authors of original works and original publication in this journal.
Для кореспонденци: Овчаренко Леонщ Серпйович, доктор медичних наук, професор, заслужений д1яч науки i техшки УкраТни, завщувач кафедри пед1атрГ|" та неонатоло-ги з курсом амбулаторноТ пед1атрГ"", Державний заклад ^<Запор1зька медична академiя тслядипломноТ осв1т^ МОЗ УкраТни», б. Вштера, 20, м. Запорiжжя, 69096, УкраТна; e-mail: [email protected]
For correspondence: Leonid Ovcharenko, MD, PhD, Professor, Honored worker of science and technology of Ukraine, Head of the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine', Vintera boulevard, 20, Zaporizhzhia, 69096, Ukraine; e-mail: [email protected]
Full list of author information is available at the end of the article.
studies have shown that VIP operates directly on the mucosal immune system, where increases IgA synthesis, indicating the critical role of this peptide in inducing oral intolerance [5].
Substance P is a peptide consisting of 11 amino acids that regulates the mucosal immune balance and chronic inflammation activity [11]. It is produced by macrophages, T-cells, dendritic cells and eosinophils. The production of substance Р by macrophages induces bacterial lipopolysac-charides [14]. Substance P is currently considered as the main neurogenic inflammatory mediator capable of causing pathophysiological reactions such as edema, mucus hypersecretion, bronchospasm, vascular tone reduction, increased permeability of postcapillary venules, immune cell penetration into the tissues and secreting glands, enhancing monocyte/macrophags chemotaxis, control of T1 response, increasing the production of interferon y [14], proinflammatory activity and secretion of tumor necrosis factor a, interleukins 1, 6, 8, 12 [9].
Another substance that has proinflammatory properties is nitric oxide (NO) — a biological messenger molecule synthesized from the amino acid L-arginine in endothelial cells, macrophages, and neurons. NO mediates a wide range of important biological processes such as vasodilation, platelet aggregation inhibition, inflammation, immunoregulation and information transmission between the central nervous system neurons and the peripheral nervous system [4, 13, 14]. NO stimulates perivascular neurogenic inflammation by facilitating the synthesis and release of immunoreactive neurotransmitters such as substance P from nociceptive afferent fibers [4]. Increasing the NO concentration in children is observed in conditions accompanied by a change in the cytokine activity — acute infection, bronchopulmonary chronic diseases, persistent intracellular infection. NO concentration in exhaled air in children correlates with neutrophilia [11]. Indirect cytotoxic effect of NO is realized due to the action of free radical derivatives — peroxynitrite, nitrogen dioxide, hydroxyl radical, which initiate lipid per-oxidation. NO metabolites — nitrates and nitrites — play an important role in the inflammation [14].
Given the role of neuropeptides in the immune response [11, 14], it is important to determine the effect of these mechanisms on the initial vegetative tone status in schoolchildren with upper respiratory tract infections (URTI). The possible neuroimmune mechanism disorders, as well as the hypodynamia effects, due to frequent exemptions from physical education classes, the prohibition of sports sections attending, and functional disorders of the cardiovascular system are the risk factors of cardiac organic pathology [3].
The purpose was to study neurogenic inflammation parameters in schoolchildren with functional disorders of the cardiovascular system and recurrent respiratory diseases.
Materials and methods
One hundred and thirty children aged 6 to 9 years were examined. The analysis of the serum VIP, substance P and the biologically active substance — NO in the form of final stable metabolites (FSM NO) was carried out.
During the observation, children were divided into three groups: group 1 — those with functional disorders of the cardiovascular system and recurrent URTI (n = 50); group 2 — patients with functional disorders of the cardiovascular system and episodic URTI (n = 50); group 3 (controls) — conditionally healthy children (n = 30).
The study of serum FSM NO (nitrates, nitrites) was carried out by restoring nitrates to nitrites with the determination of the latter in reaction with the Griess reagent. The optical length was measured on spectrophotometer at a wavelength of 540 nm. Calculation of nitrite amount was carried out according to the calibration graph built on nitrogen. A quantitative determination of serum substance P and VIP was carried out by the immunoassay on Sunrise photometry analyzer (TECAN, Austria) using the ELISA kits (Peninsula Laboratories, LLC, San Carlos, USA).
The study uses statistical methods for information processing obtained: Fischer's angle criterion, mean (M), mean error (m), Student's i-test, Mann-Whitney f-test. ROC analysis of diagnostic tests was performed based on calculating the predictive value of the area under the ROC curve (AUC) with a cut-off point calculation.
Results
The examination of schoolchildren was carried out during the period of somatic well-being. The results of the study are presented in Table 1.
When determining serum levels of substance P, VIP, FSM NO in group 1 children in the period of somatic well-being, there was a statistically significant (compared to group 3) increase in substance P concentration, FSM NO and a decrease in VIP content (p < 0.05). At the same time, a decrease in the serum VIP was noted compared to study group 2 (p < 0.05).
Analyzing the levels of substance P in children with recurrent and episodic URTI, one can conclude that no significant difference was found (U = 1071.0; p > 0.05), this is confirmed by the data of ROC analysis (Fig. 1).
Table 1. Neurotransmitter serum content in children, ng/ml (M ± m)
Indicators Groups
1 (n = 50) 2 (n = 50) 3 (n = 30)
Substance P 0.48 ± 0.06** 0.44 ± 0.03 0.41 ± 0.04
VIP 0.27 ± 0.02*, ** 0.34 ± 0.02 0.38 ± 0.03
FSM NO 21.23 ± 1.11** 20.30 ± 1.17 17.67 ± 1.04
Notes: * — p < 0.05 — when compared with the results of group 2; ** — p < 0.05 — when compared with the results of group 3.
ROC analysis of substance P serum concentration distribution between the 1 and 2 observation groups showed that the cut-off point was 0.31 ng/ml. Higher levels of substance P are associated with an increased risk of recurrent URTI. The optimal cut-off point is 0.31 ng/ml (AUC 0.6) with sensitivity of 26.0 % and specificity of 90.0 % (Fig. 1).
Among children with recurrent URTI and control group, there is a statistically significant difference in the concentration of substance P (U = 529.5; p < 0.05). Also, these differences in results are confirmed by data from ROC analysis (Fig. 2). ROC analysis of the distribution of substance P content in groups 1 and 3 showed that cut-off point is 0.3 ng/ml. Higher levels of substance R are associated with an increased risk of recurrent URTI. The optimal cutoff point is 0.3 ng/ml (AUC 0.7) with sensitivity of 33.0 % and specificity of 100.0 % (Fig. 2).
Determination of serum VIP in children of groups 1 and 2 showed significant differences, as evidenced by data of ROC analysis (Fig. 3).
Cut-off point for the serum concentration of VIP was determined, which corresponds to the level of 0.34 ng/ml. Lower levels are associated with an increased risk of recurrent URTI (AUC 0.8) with sensitivity of 68.0 % and specificity of 100.0 %. Similar results are obtained when comparing groups 1 and 3. The differences are also confirmed by ROC analysis data (Fig. 4). The cut-off point for VIP serum concentration is 0.28 ng/ml. VIP indices below this index will be associated with the risk of developing recurrent URTI (AUC 0.8) with sensitivity of 100.0 % and specificity of 50.0 %.
The determination of FSM NO serum content showed a slight difference between groups 1 and 2 (U = 873.0;
Figure 1. Sensitivity and specificity of the threshold value of serun substance P in groups 1 and 2
Figure 3. Sensitivity and specificity of the threshold value of serum VIP in groups 1 and 2
Figure 2. Sensitivity and specificity of the threshold value of serum substance P in groups 1 and 3
Figure 4. Sensitivity and specificity of the threshold value of the serum VIP in groups 1 and 3
p > 0.05) and the reliable differences between groups 1 and 3 (U = 377.5; p < 0.05). The conducted ROC analysis determined the cut-off point for FSM NO in the comparison groups 1 and 2 — 18.11 ng/ml. Serum concentration of FSM NO above this indicator was associated with an increased risk of recurrent URTI (AUC 0.7) with sensitivity of 44.0 % and specificity of 90.0 % (Fig. 5).
When comparing the indicators in groups 1 and 3, the serum level of FSM NO was 16.99 ng/ml by the cut-off point. Excess of this concentration is associated with a high risk of recurrent URTI (AUC 0.75) with sensitivity of 63.0 % and specificity of 100.0 % (Fig. 6).
Discussion
The inflammation pathogenesis goes beyond the scope of immune mechanisms — neuronal interactions are involved in this process. This is due to the ability of immu-nocompetent cells stimulated by inflammation to produce neuropeptides similar to those produced in the central nervous system [5]. Some neuropeptides/neurotransmitters have anti-inflammatory properties — one of them is VIP, and proinflammatory properties such as substance P and NO [8, 10, 14].
Based on the current theory of neuro-endocrine-im-mune regulation, immune responses can be considered as components of neuroendocrine activity, and by themselves they are impossible without the cohesive participation of the nervous and endocrine systems. Humoral regulatory factors affecting both of these systems are involved in the implementation of neuroimmune interactions [12].
Recurrent URTI in schoolchildren has a negative effect on the functional status of respiratory, cardiovascular, central nervous systems, changing the mechanism of pathological process, which is clinically manifested by the delayed recovery. The need to study the serum levels of neurotrans-mitters in schoolchildren with recurrent URTI allowed us to determine the degree of participation of neuro-immune
inflammation in the pathogenesis of the disease and to allocate a risk group for the development of recurrent respiratory tract diseases. A comparative analysis of the serum substance P in schoolchildren showed significant differences between group 1 and the control group (p < 0.05). Exceeded the established concentration of substance P increases the risk of recurrent diseases.
The proinflammatory orientation of FSM NO, especially in children of group 1, may increase the activity of neurogenic inflammation. Probably, this due to the fact that in children with recurrent URTI on the background of increased activity of immunocompetent cells as a result of prolonged viral-bacterial stimulation, the production of central nervous system transmitters increased in response to a stressful situation, which is linked with recurrent diseases [12]. Exceeding established concentration of FSM NO increases the risk of recurrent URTI.
A significant decrease in the content of anti-inflammatory transmitters, in particular VIP, in children with recurrent URTI can not suppress the activity of neurogenic inflammation.
Conclusions
1. In schoolchildren aged 6 to 9 years with recurrent URTI in the somatic well-being period, there is an increase in the serum concentration of neuroimmune proinflamma-tory mediators — substance P and FSM NO.
2. The period of somatic well-being in schoolchildren aged 6 to 9 years with recurrent URTI is characterized by a decrease in the concentration of anti-inflammatory neuropeptide VIP.
3. ROC analysis is a mechanism for predicting the risk of recurrent URTI.
Conflicts of interests. Authors declare the absence of any conflicts of interests that might be construed to influence the results or interpretation of their manuscript.
Figure 5. Sensitivity and specificity of the threshold concentration of FSM NO in groups 1 and 2
Figure 6. Sensitivity and specificity of the threshold value of FSM NO in children groups 1 and 3
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Received 03.06.2019 ■
Information about authors
Leonid Ovcharenko, MD, PhD, Professor, Honored worker of science and technology of Ukraine, Head of the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine'; Zaporizhzhia, Ukraine; e-mail: [email protected] Denis Sheludko, PhD, Assistant at the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine'; Zaporizhzhia, Ukraine; e-mail: [email protected]
Andrei Vertehel, MD, PhD, Associate Professor at the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine'; Zaporizhzhia, Ukraine; e-mail: [email protected]
Igor Samokhin, PhD, Associate Professor at the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine'; Zaporizhzhia, Ukraine; e-mail: [email protected]
Tatiana Andrienko, PhD, Associate Professor at the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine'; Zaporizhzhia, Ukraine; e-mail: [email protected]
Alexander Kryazhev, PhD, Assistant at the Department of pediatrics and neonatology with course of outpatient pediatrics, State Institution "Zaporizhzhia Medical Academy of Postgraduate Education of the Ministry of Health of Ukraine', Zaporizhzhia, Ukraine; e-mail: [email protected]
ОвчаренкоЛ.С., Шелудько Д.М., Вертегел А.О., Самохн 1.В., Ahapîchko Т.Г., Кряжев О.В. ДЗ «3anopÎ3bi<a медична академiя пслядипломноÏ освти МОЗ Укра'ни», м. Запоржкжя, Укра'на
^poBOTKOBi концентраци нейротрансм1терш у дгтей ¡з рекурентними Ыфекщями верхых дихальних шляхiв
Резюме. Актуальшсть. Дгги молодшого шильного вшу схильш до частих захворювань оргашв дихання. У структурi загально! захворюваносп ця патологш посщае перше мюце. II поширешсть становить понад 60 %, що призводить до час-тих пропускав школи, вщсутносй активних тер i прогулянок на св1жому повг^. Зважаючи на це збшьшуеться ильисть часу, який дитина витрачае на засоби масово! електронно! комушкацй i електронш ^ри, що призводить до високо! при-хильносп, навиь до залежносп, формуючи гшодинамш та пщвищення психоемоцшного напруження, що в сукупнос-п мае негативний вплив на функцюнування регуляторних систем дитячого оргашзму. Рекурентш шфекци верхнгх дихальних шляхiв (1ВДШ) викликають напруження нейроен-докринно4мунно! регуляцй, що призводить до дисбалансу нейропептидiв — медiаторiв нейрогенного запалення. Метою ще! роботи е вивчення показниив нейрогенного запалення у школярiв молодших клаав iз рекурентною патолоп-ею рестраторного тракту. Матерiали та методи. Ми обсте-жили 130 дией iз рекурентними 1ВДШ вшом вщ 6 до 9 роив у перюд соматичного благополуччя. Проведено аналiз умюту вазоактивного штестинального пептиду (В1П), субстанцй Р
i кшцевих стабшьних метаболтв оксиду азоту (КСМ NO) у сироватщ KpoBi. Виявлено пщвищення piBM субстанцй Р у школярiв i3 рекурентними 1ВДШ, що мало статистично вь рогщт вщмшносп i3 показниками умовно здорових дитей (р < 0,05). Результата. Установлено, що за високих концен-трацш субстанцй Р пщвищуеться ризик розвитку повторних захворювань. Доведено, що в дгтей iз рекурентними 1ВДШ за рахунок пщвищення сироваткового вмюту КСМ NO, яи мають прозапальну спрямовашсть, посилюеться актившсть нейрогенного запалення. Виявлено, що при вiроriдному зниженш вмюту В1П як протизапального трансмиера в дитей iз рекурентними 1ВДШ неможливе пригтчення активносп нейрогенного запалення, що призводить до його надмiрноï стимуляци. Висновки. Дии з рекурентними 1ВДШ у перюд соматичного благополуччя мають пщвищеш концентраци субстанцй Р i КСМ NO в плазмi кровi. У перюд соматичного благополуччя в дгтей раннього шильного вшу з рекурентними 1ВДШ спостертаеться зниження рiвня протизапального нейропептиду В1П.
Ключовi слова: дгга; нейропептиди; субстанц1я Р; реку-рентш iнфекдïï верхн1х дихальних шлях1в
ОвчаренкоЛ.С., Шелудько Д.Н., Вертегел А.А., Самохин И.В., Андриенко Т.Г., Кряжев А.В.
ГУ «Запорожская медицинская академия последипломного образования МЗ Украины», г. Запорожье, Украина
Сывороточные концентрации нейротрансмиттеров у детей с рекуррентными инфекциями верхних дыхательных путей
Резюме. Актуальность. Дети младшего школьного возраста подвержены частым заболеваниям органов дыхания. В структуре общей заболеваемости данная патология занимает первое место. Ее распространенность составляет более 60 %, что приводит к частым пропускам школы, отсутствию активных игр и прогулок на свежем воздухе. Ввиду этого увеличивается количество времени, которое ребенок тратит на средства массовой электронной коммуникации и электронные игры, что приводит к высокой привязанности, вплоть до зависимости, формируя гиподинамию и повышение психоэмоционального напряжения, что в совокупности оказывает негативное влияние на функционирование регуляторных систем детского организма. Рекуррентные инфекции верхних дыхательных путей (ИВДП) вызывают напряжение нейроэндокринно-им-мунной регуляции, что приводит к дисбалансу нейропепти-дов — медиаторов нейрогенного воспаления. Целью данной работы является изучение показателей нейрогенного воспаления у школьников младших классов с рекуррентной патологией респираторного тракта. Материалы и методы. Мы обследовали 130 детей с рекуррентными ИВДП в возрасте от 6 до 9 лет в период соматического благополучия. Проведен анализ содержания вазоактивного интестинального пептида
(ВИП), субстанции Р и конечных стабильных метаболитов оксида азота (КСМ NO) в сыворотке крови. Выявлено повышение уровня субстанции Р у школьников с рекуррентными ИВДП, которое имело статистически достоверные различия с показателями условно здоровых детей (р < 0,05). Результаты. Установлено, что при высоких концентрациях субстанции Р повышается риск развития повторных заболеваний. Доказано, что у детей с рекуррентными ИВДП за счет повышения сывороточного содержания КСМ NO, имеющих провоспали-тельную направленность, усиливается активность нейроген-ного воспаления. Выявлено, что при достоверном снижении уровня ВИП как противовоспалительного трансмиттера у детей с рекуррентными ИВДП невозможно подавление активности нейрогенного воспаления, что приводит к его чрезмерной стимуляции. Выводы. Дети с рекуррентными ИВДП в период соматического благополучия имеют повышенные концентрации субстанции Р и КСМ NO в плазме крови. В период соматического благополучия у детей раннего школьного возраста с рекуррентными ИВДП наблюдается снижение уровня противовоспалительного нейропептида ВИП. Ключевые слова: дети; нейропептиды; субстанция Р; рекуррентные инфекции верхних дыхательных путей
