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Peculiarities of the changes of the values of nitric oxide system in children with Mycoplasma pneumonia associated...
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Tadjikhanova Dono Pulatovna, Junior scientific assistant of the Republican specialized scientific-practical medical center of Pediatrics of the Ministry of Health Care of the Republic of Uzbekistan
E-mail: [email protected]
Peculiarities of the changes of the values of nitric oxide system in children with Mycoplasma pneumonia associated with Herpes viral infection
Abstract: The article represents the data of nitric oxide system in children with Mycoploasma pneumonia associated with Herpes viral infection. A reliable rise of nitric oxide level and peroxynitrite was established. More explicit values were noted in the patients with HSV and CMV association, and it coincides with clinical progress of endotoxicosis and lesion of various organs and systems.
Keywords: Mycoplasma pneumonia, Herpes viral infection, children.
Extra hospital pneumonia is the most widely spread group of pneumonias. In spite of constant upgrading of diagnostic methods and availability of modern very effective antimicrobial agents, in developed countries extra hospital pneumonia still occupies a leading place in the structure of morbidity and lethality of infectious diseases [2; 4; 5]. Recently the role of Mycoplasma pneumonia (MP) played in the development of bronchial pulmonary diseases in children is growing and it takes from 8 to 25% of all cases, and in isolated and semi-isolated groups — up to 50% [1; 3; 6]. Pathogenesis of Mycoplasma infection depends on the direct action of the agent on various organs and systems, and it also consists of interrelation of toxins, enzymes and development of auto immune reactions. Mostly Mycoplasma pneumonia is combined with Herpes viral infections, the result of which is an impact on an organism of two or more agents of viral, bacterial or other etiology [10].
Nitric oxide (NO) and its derivatives, as well as active forms of oxygen, are key pathogenetic factors of an infection, inflammation and malignant growth [7, 8]. K. Mayeda, T. Akaike (1998) in their review presented the data demonstrating that NO, superoxide and the product of its reaction — peroxynitrite, appearing in cases of infectious diseases, take a
great part in the development and pathogenesis of diseases: they become mediators of inflammation, modify proteins and damage nucleic acids [11; 12]. In the literature there is a great number of publications, dedicated to the part of nitric oxide in pneumonias with various etiologies, mostly among adult patients. Though, there are no peculiar changes of No-ergic system in children with mixed-infectious pneumonia.
The aim of the research: is to study the peculiarities of changes of NO-ergic system in children with Mycoplasma pneumonia associated with Herpes viral infection.
Material and the methods of the research: the follow-up covered 195 children aged from one to three years old with Mycoplasma pneumonia (MP) associated with Herpes viral (HSV) (80 children — 1st group), cytomegalovirus (CMV) (65 children — 2nd group) or their association (50 children — 3rd group) during active stage of the disease, getting clinical therapy in pulmonologic department of RSSPMC of pediatrics.
Clinical diagnosis of Mycoplasma pneumonia was set taking into account clinical anamnestic and additional laboratory and radiologic data. Status of 26 children was mild severe, and severe in 65 children. The most severe progress of the disease was observed among the patients with MP+CMV+HSV.
Section 7. Medical science
For the establishment of diagnosis we took into account anamnestic data, results of clinical, laboratory, functional and immunologic research methods.
Specific diagnostics of an infection presence was performed by means of the immune enzyme analysis (IEA) method in reference laboratory of RSSPMC and PCR method in Immunology Institute of AS of the RUz.
Control group involved 30 almost healthy children of the corresponding age. Biochemical analysis included detection of NO content according to the sum of nitrites and nitrates metabolites (NO2 and NO3), in Metelski V. A. et al. modification definition of nitric oxide synthase (eNOS) activity; nitrate reductase (NR); and the level of peroxynitrite (ONOO-).
Statistic processing of the results of the research was performed with the help of «Microsoft Excel XP» and «Statis-tica 6,0».
Results and discussion: Mycoplasma pneumonia in young children was accompanied by explicit clinical manifestations of endotoxicosis, especially in the group of children with association of several viruses.
In 9.4; 10.7 and 14.8% of children of the 1st, 2nd and 3rd groups we registered dry mucous membranes of the upper respiratory ways, dry torturing coughing and conjunctivitis.
More than half of these children — in 50; 57.1 and 66.7%
Table 1. - Content of nitric oxide system in
cases — had explicit bronchial obstruction syndrome, displayed clearly in the radiologic images.
Inflammatory process had right side location in 56.3; 46.4 h and 44.4% cases, bilateral in 34.3; 46.5 and 48.2% of the patients, left side in 9.4; 7.1 and 7.4% of the children, correspondingly to the groups.
Radiologically 53.1; 57.1 and 70.4% of the children had infiltration of pulmonary tissue. In the rest cases there was detected deformation and turbid pulmonary picture, intensification of vascular component and interstitial alterations.
The values of hemogram were characterized by erythro-penia, neutropenia, moderate Leukocytosis with symptoms of eosinophilia, monocytosis, lymphocytosis, and in some cases leucopenia with lymphocytopenia, acceleration of ESR, testifying the presence of inflammatory process in organisms of the children with explicit decrease of immune reactivity.
In the children with MP combined with Herpes viral infection we observed a rise of nitric oxide metabolism terminal products' level. Degree of it depended on the group of the agents. Thus, ifthat value raised 1.29 times in the children of the 1st group in comparison with the data of healthy children, in the children of the 2nd group the rise was equal to 1.4 times, and in the 3rd group — 1.63 times. CMV infection, especially combined with HSV significantly raised production of nitric oxide.
children with Mycoplasma pneumonia, M±m
Groups Content of the products Enzyme activity
NO2(NO3), Mkmol\l ONOO-, mkmol\l eNOS, mkmol\min*mg of protein HP, mkmol\min*mg of protein
Control group, n=20 9.67±0.43 0.08±0.003 16.88±0.87 0.22±0.005
1st, n=32 12.47±0.48 a 0.15±0.006 a 12.57±0.36 a 0.32±0.011 a
2nd, n=28 13.49±0.39 a 0.18±0.006 a 12.30±0.31 a 0.39±0.007 a
3rd, n=27 15.75±0.24 a, 6, B 0.33±0.007 a, 6, B 9.45±0.51 a, 6, B 0.48±0.011 a, 6
Note: a- difference between the values of almost healthy and sick children are reliable (P<0.001), 6 — differences are reliable for the 1st group, b — differences are reliable for the values of the 2nd group.
It should be noted, that in spite of the raised NO production, we observed inhibition of eNOS 1.34; 1.37 and 1.79 times in blood serum of the children of the 1st, 2nd and the 3rd groups, correspondingly. And it was observed more in the cases of mixed infection.
According to the reference data, generation ofNO high concentrations demonstrates cytotoxic activity as one ofcell-mediat-ed immunity effectors [4; 7]. Synthesis of it in the amounts like that is provided by inducible isoform ofNOS, synthesized in immune competent and other cells and tissues under the influence of cytokines and other biologically active substances.
Actually, activity of NR in the blood of 1st group children raised 1.45 times, 2nd group children — 1.77 times and especially among the patients of the 3rd group — 2.18 times in comparison with the values of almost healthy children.
Disorders of enzyme generation of NO. Cause disorders conditioned, first of all, by the ability of all NOS isoforms to produce superoxide-radical together with nitric oxide.
The following reaction of these products leads to formation of toxic agent ONOO- with high oxidative activity. In case of
nitric oxide and superoxide generation by one and the same system the possibility of interaction increases, and these enzymes can contribute much to the formation of ONOO- in the cells and tissues, which often becomes the reason of cell death.
For the detection of that we determined the amount of ONOO- in blood of sick children with mixed pneumonia. The analysis performed for that showed the rise of its amount 1.87 times in the children of the 1st group. A greater rise we could observe among the children of the 2nd group with combination of MP and CMV, and its level statistically significantly increased 2.25 times. A sudden rise of that compound we noted among the children of the 3rd group with the combination of MP with CMV and HSV. That value increased 2.2 and 1.83 times in relation to the values of the 1st and 2nd groups and 4.22 times in comparison with the values of healthy children.
In usual conditions formation of ONOO- is not intensive, as an endogenic super oxide dysmutase deletes superoxide radical. Though, in case of inflammation activated leukocytes and other cells can produce great amounts of superoxide.
Peculiarities of the changes of the values of nitric oxide system in children with Mycoplasma pneumonia associated.
High concentrations of it inhibit aconitase and cellular breathing, it oxidizes biologic tioli, causes raptures of DNA chains, exhausts the level of NAD and ATP, and causes disorder of intra cellular signaling processes, promoting acceleration of apoptosis.
Experimental researches with mice infected by influenza virus or effected by liposaccharides revealed a hundred times rise ofxantine oxidase activity in bronchial alveolar lavage leading to significant generation of super oxide. At the same time the authors observed activation of inducible NOS, leading to the rise of NO- concentration and as a result sudden rise of ONOO-.
On the basis of the achieved data it was detected that more intensive production of nitric oxide and peroxinitrite is more characteristic for the children of the 2nd and 3rd groups, and obviously, conditioned by toxic effect of CMV, as it damages blood cells, epithelial cells, and freely moves to vascular endothelium, conditioning ischemia and hemorrhages to various tissues, especially in combination with HSV.
The results achieved in the process of the performed research correlate with the degree of clinical manifestation
of intoxication, involvement of gastro-intestinal system, liver and kidneys to the pathologic process, and development of metabolic encephalopathy. Evidently, the development of secondary infection, rising the amount of active population of lymphocytes, leads to the expression of acute stage cytokines, inducing formation of super oxide and peroxynitrite and significantly accelerating cell apoptosis.
On the basis of the achieved data we can conclude the following:
1. Children with Mycoplasma pneumonia associated with Herpes infection had notable rise of nitric oxide and peroxynitrite. More expressed values were noted among the patients with MP+HSV+CMV association, and that coincides to the clinical symptoms of endotoxicosis and lesion of various organs and systems.
2. Hyper production of toxic metabolites of NO-ergic system in children with Mycoplasma pneumonia, associated with Herpes viral infection conditioned by the expression of nitric oxide inducible synthase, especially with HSV+CMV
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