Clinical Significance of Changes in Cytokine and Nitric Oxide Levels in Chronic Lung Diseases in Children

The dissertation is devoted to the study of the clinical significance of changes in cytokine and nitric oxide levels in chronic bronchopulmonary pathology in children. The research analyzes the dynamics of endogenous production of pro-inflammatory and anti-inflammatory interleukins, transforming growth factor-beta 1, and nitric oxide metabolites in serum blood and bronchoalveolar lavage fluid in various forms of chronic bronchopulmonary pathology, including chronic pneumonia, congenital malformations of the lungs, and alveolitis. The work substantiates the diagnostic significance of a comprehensive analysis of the aforementioned biomarkers for the assessment of inflammatory process activity, the determination of the extent of the bronchopulmonary process, and the monitoring of the efficacy of complex anti-inflammatory therapy in children.

Relevance of the Problem: Chronic inflammatory lung diseases (CILD) constitute a pressing problem in pediatrics, as the frequency of these conditions has been increasing in recent years, and their clinical manifestations are characterized by severe disease course and early disability of patients (Rachinsky S.V., 1998; Studenikin M.Ya., 1998; Tatchenko V.K., 2002; Volkov I.K., 2003).

The underlying basis of CILD is an inflammatory process of infectious origin occurring against the background of structural changes in the lung and bronchial tissues. Frequently, the course of the underlying disease is complicated by the superimposition of a bronchoobstructive syndrome, respiratory insufficiency, and allergic conditions, which aggravate the course of the illness (Kaganov S.Yu., Rozinova N.N., 1999; Sereda E.V., 1999; Volkov I.K., 2004).

In connection with this, particular significance is acquired by the search, development, and implementation of novel methods for the diagnosis and treatment of these diseases. One of the modern methods for determining the activity of inflammation in chronic forms of bronchopulmonary pathology is the quantitative analysis of biologically active compounds as markers of the inflammatory process, which may also be employed in the evaluation of the efficacy of anti-inflammatory therapy for these diseases in children (Smirnov I.E., 2002; Demyanov A.B., 2003). It is precisely for this reason that pulmonology is undergoing a period of vigorous development of fundamentally novel diagnostic methods for virtually all forms of respiratory system pathology. The emergence of new diagnostic methods is associated with the realization of measures for early diagnosis and prevention of the principal nosological forms of pulmonary diseases (Sokh F.E., 1997; Boggs S.E., 1998).

In recent years, increasing attention has been attracted by cytokines — biologically active compounds that influence the development of the inflammatory reaction, processes of cellular proliferation, and participate in the realization of endogenous immunoregulation.

The basis of processes determining the inflammatory-reparative changes in the respiratory system lies in local and systemic reactions regulated by means of intercellular interactions mediated by both pro-inflammatory and anti-inflammatory cytokines — interleukins (IL), transforming growth factor-beta 1 (TGF-beta1), and nitric oxide (NO), among others (Flynn J.L., 1994; Kerwin J.F., 1995; Stcindiford T.J., 1996; Hayashi T., 1997; Eboriadou M., 1998; Russel D.G., 1998; O'Brien D.P., 1999; Arva E., 1999; Chuchalin A.G., 2002).

A definite quantity of cytokines is necessary for an adequate immune response and protection in the case of lung pathology. Disruption of the production and receptor function of anti-inflammatory cytokines leads to profound defects of anti-infectious protection, up to the development of an immunodeficient state, and aggravates the direct damaging action of microorganisms and their toxins on pulmonary tissue (Abbas A., 1991; Thomson A., 1992; Freydlin I.S., 2000; Geltser B.I., 2002).

However, to date, the degree of involvement of various regulators of inflammation in the formation and progression of chronic lung diseases in children remains insufficiently studied; therefore, the investigation of the dynamics of production of these compounds appears important for the diagnosis and enhancement of the efficacy of treatment of these forms of pathology. The resolution of the indicated questions is also necessary for the development of an optimal therapeutic strategy for the prevention of exacerbation of the chronic bronchopulmonary process, which determined the objective of this work:

To establish the patterns of changes in endogenous production of cytokines and nitric oxide in chronic lung diseases in children, in order to evaluate the activity of the inflammatory process and enhance the efficacy of anti-inflammatory therapy.

Research Objectives

1. To study the dynamics of cytokine and nitric oxide metabolite levels in serum blood in various forms of chronic lung diseases in children.

2. To determine changes in cytokine and nitric oxide metabolite levels in bronchoalveolar lavage fluid in children with congenital malformations of the bronchi and lungs.

3. To establish changes in cytokine and nitric oxide metabolite production depending on the activity and extent of the chronic bronchopulmonary process.

4. To evaluate the influence of complex therapy on endogenous cytokine and nitric oxide production in patients with chronic lung diseases.

Scientific Novelty

For the first time, changes in endogenous production of interleukins, transforming growth factor-beta 1, and nitric oxide metabolites were comprehensively studied, and the diagnostic significance of their determination in children with various forms of chronic bronchopulmonary pathology was substantiated.

It was established that exacerbation of the chronic inflammatory bronchopulmonary process in children is caused by the activation of persistent microflora (Haemophilus influenzae, Streptococcus pneumoniae, and Moraxella catarrhalis) and is accompanied by a significant increase in the content of interleukins (IL-6 and IL-8) in blood and bronchoalveolar lavage fluid (BALF), which does not depend on the type of infectious pathogen.

For the first time, it was revealed that a substantial elevation in the content of interleukins and nitric oxide metabolites in blood and bronchoalveolar lavage fluid in children with chronic lung diseases is an indicator of high activity of the inflammatory process and depends on its extent.

For the first time, it was established that hyperproduction of pro-inflammatory interleukins (IL-6, IL-8), persisting during convalescent observation in children with various forms of bronchopulmonary pathology, constitutes a criterion for selecting patients for targeted course therapy and rehabilitation.

A significant decrease in the content of cytokines and nitric oxide metabolites in the serum of patients following complex treatment of chronic bronchopulmonary diseases in children is an indicator of the efficacy of anti-inflammatory therapy.

Practical Significance of the Work

The necessity of a comprehensive analysis of cytokines and nitric oxide metabolites for an adequate assessment of inflammation activity and for determining the efficacy of complex therapy of chronic inflammatory lung diseases in children has been demonstrated.

The established concentrations of interleukins, transforming growth factor, and nitric oxide metabolites in blood and bronchoalveolar lavage fluid are, for the first time, proposed as criteria of inflammatory process activity in chronic forms of bronchopulmonary pathology in children.

Additional indicators for evaluating the extent of the bronchopulmonary process have been proposed on the basis of monitoring the content of pro-inflammatory interleukins and nitric oxide in blood.

A decrease in the concentrations of interleukins and nitric oxide metabolites against the background of complex therapy of CILD in children constitutes evidence of the efficacy of the conducted treatment.

The established patterns of changes in cytokine and nitric oxide metabolite content are recommended for use in monitoring the clinical course of CILD and in optimizing the therapy of these forms of pathology in children.

Implementation in Practice: Quantitative determination of levels of pro-inflammatory, pro-sclerotic, and anti-inflammatory factors in serum blood and bronchoalveolar lavage fluid in children with chronic lung diseases has been introduced into the practical activities of the pulmonology department, the laboratory of general pathology of the Research Institute of Pediatrics of the State Unitary Enterprise "Research Center for Children's Health" of the Russian Academy of Medical Sciences, and is recommended for wide use in pediatric practice.

The principal provisions of the dissertation were presented and discussed at the III Scientific-Practical Conference "Questions of Preventive Medicine in the Regions of the Far North" (Nadym, 2003); at scientific-practical conferences of Russian pediatricians (Moscow, 2004, 2005); at the II National Scientific-Practical Conference with international participation (Izhevsk, 2005); at the X Congress of Russian Pediatricians (Moscow, 2005); at the IV Russian Congress "Modern Technologies in Pediatrics and Pediatric Surgery" (Moscow, 2005).