Markers of Oxidative Stress at the Irreversible Stage of Chronic Obstructive Pulmonary Disease. Approaches to Correction

The dissertation is dedicated to the study of markers of oxidative stress at the irreversible stage of chronic obstructive pulmonary disease (COPD) and the development of approaches to their correction. The study analyzes the state of the pro- and antioxidant system of blood, leukocyte bactericidal activity (oxygen-dependent and oxygen-independent), the level of nitric oxide, and indicators of oxidative stress in patients with severe irreversible COPD in the dynamics of the disease. Special attention is given to the evaluation of the effectiveness of complex antioxidant therapy, which includes the use of antioxidants (alpha-tocopherol, ascorbic acid) in combination with the ion-exchange sorbent "Lithovit." The scientific work is aimed at the objective assessment of the severity of oxidative stress and the development of evidence-based correction schemes directed at stabilizing the balance of "oxidants-antioxidants" and improving the quality of life of patients.

Chronic Obstructive Pulmonary Disease is a disease of the respiratory system behind which stands one of the most serious problems of theoretical and practical medicine of the 21st century (Chuchalin A.G., 2000; Shmelev E.I., 2000; "Chronic." ed. Kokosov A.N., 2002; Aisanzov Z.R., 2003; Wilkens N. et al., 2003; Robin J. et al., 2003; Cosentino F. et al., 2003). Only in the United States from 1979 to 1991, mortality from chronic obstructive pulmonary disease (COPD) increased by 32.9% (Burney R., 1993). In Russia, in the general structure of respiratory diseases in 1996, COPD ranked 13th, accounting for 12.3% of total morbidity (Shmelev E.I., 2000). Mortality in approximately those years was: in 1985 - 11.5; 1989 - 11; 1991 - 14.5; 1993 - 20.1; 1995 - 14.1; 1997 - 11.5 per 100,000 population ("Chronic." ed. Kokosov A.N., 2002). The economic damage from this disease is truly enormous, and statistical data on the prevalence of COPD are approximate due to the imperfection of mass epidemiological studies (National Center for Health Stat. Cur.est., 1995; Soriano J.R. et. al., 2000; Volkova L.I. et al., 2003). This explains the fact that the problem of COPD attracts the interest of scientists worldwide, and in the course of numerous studies a wide range of questions is discussed, from definitions of its essence to problems of providing care and prevention of this disease.

The mechanisms of inflammation play a special role in the progression of COPD. On the one hand, this is a universal reaction to the action of all known and presumed risk factors; on the other hand, this is the main cause of all functional and morphological manifestations of the disease. Practically all cellular elements of the respiratory system, activated under the influence of etiological factors, participate in the inflammatory process. But in the complex cellular cooperation, the key role belongs to neutrophils, which act as detectors of inflammation, its intensity, kinetics, and trends of development. The phagocytic function of neutrophils is associated with the release of an enormous amount of pro-inflammatory mediators and a range of substances possessing powerful destructive action on all molecular components of tissues. This, first and foremost, includes neutral and acidic proteases, defensins, and oxygen radicals, leading to the destruction of alveoli and epithelial cells of the bronchial mucosa. The release of an excessive amount of free radicals exceeding physiological needs leads to the development of oxidative stress and the depletion of antioxidant defense mechanisms in the lungs. In turn, oxidative stress and the disturbance of equilibrium in the systems: "proteases-antiproteases" and "oxidants-antioxidants" maintain the inflammatory process in bronchopulmonary tissue and contribute to the relentless progression of morpho-functional disorders in the respiratory system.

The effectiveness of therapeutic measures for halting the progression of COPD depends fully on the possibility of treating chronic inflammation. Classical therapy of chronic obstructive pulmonary disease has at its disposal medicinal preparations meeting strict safety requirements. These include: the modern generation of sympathomimetics and cholinolytics, xanthine derivatives, inhaled corticosteroids, and agents regulating the formation of bronchial secretion, as well as antibiotic therapy ("Federal Program.", 1999). The use of antioxidants is also provided for in the recommendations of the European Society for the Diagnosis and Treatment of Obstructive Lung Diseases (1995). However, to date, the results of multicenter randomized studies in which the effectiveness of the use of antioxidants in COPD patients would be fully proven have not been obtained. Many mechanisms of action of antioxidants remain unclear. To an even greater extent, the data on the assessment of the effectiveness of the use of antioxidants in chronic obstructive pulmonary disease are ambiguous and fragmented (Dunster S., Kelly F.J., 1994; Chambers D.C., Ayres J.G., 2001).

One of the promising directions of action on free radical oxidation processes through the correction of exchange of metals of variable valence is considered to be the use of biologically active supplements with ion-exchange properties. In recent decades, increasing attention is being paid to the dependence of the activity of the immune system on the adequate supply of the organism with microelements. However, methods of influencing microelement exchange for the correction of free radical oxidation processes remain largely unexplored (Kudrin A.B. et al., 2000).

In connection with this, the use of biologically active supplements with ion-exchange properties, possessing a unique stabilizing influence on the exchange of microelements participating in the formation of cofactors of active centers of key antioxidant enzymatic systems of the organism, appears promising as part of complex antioxidant therapy (Mayanskaya N.N., Novoselov Ya.B., 2000).

Thus, the development of approaches to effective correction of irreversible chronic obstructive pulmonary disease directly depends on the successes in studying the mechanisms of anti-inflammatory and antioxidant defense, and the knowledge of methodology and scientific-practical foundations of the action of antioxidants on the human organism will allow their rational use in complex therapy of this severe disease.

Goal of the Study

To identify the characteristics of the state of the pro- and antioxidant system in patients with the irreversible stage of chronic obstructive pulmonary disease in the dynamics of the disease and to develop approaches to their complex correction.

Tasks of the Study

1. To assess the state of oxygen-dependent and oxygen-independent leukocyte bactericidal activity in patients with the irreversible stage of chronic obstructive pulmonary disease in the dynamics depending on various methods of correction.

2. To assess the pro- and antioxidant activity of blood in the dynamics of the disease depending on the conducted therapy.

3. To determine the level of nitric oxide in the serum of blood in patients with the irreversible stage of chronic obstructive pulmonary disease and to evaluate it in the dynamics depending on the method of correction.

4. To evaluate the clinical effectiveness of complex therapy with the use of antioxidants and sorbents with ion-exchange properties in patients with the irreversible stage of chronic obstructive pulmonary disease.

Scientific Novelty

It has been demonstrated that the course of severe irreversible chronic obstructive pulmonary disease is accompanied by the depletion of bactericidal activity of blood leukocytes, manifested in the decrease of spontaneous and zymosan-stimulated chemiluminescence, the reduction of the leukocyte stimulation index, and the opsonic activity of blood plasma.

For the first time, it has been discovered that oxidative stress at the irreversible stage of chronic obstructive pulmonary disease throughout the entire observation period manifests itself as a significant imbalance in the state of pro- and antioxidant mechanisms and the depletion of the reserve of total nitric oxide fraction in blood serum.

An inverse correlation relationship has been identified between the low level of total nitric oxide fraction and the high content of malondialdehyde, as well as a direct correlation relationship between the low level of nitric oxide and low antioxidant activity of blood in patients with exacerbation of severe chronic obstructive pulmonary disease.

It has been found that the irreversible stage of chronic obstructive pulmonary disease is accompanied by the acceleration of the degranulation process, evidenced by the reduction of the mean cytochemical coefficient of the leukocyte-cationic test, accompanied by an increase in the level of lactoferrin and acid phosphatase activity in blood serum.

For the first time, the dynamics of oxygen-dependent and oxygen-independent leukocyte activity in patients with the irreversible stage of chronic obstructive pulmonary disease depending on the volume of antioxidant therapy and the complex of antioxidants + "Lithovit" has been studied, revealing a stimulating and modulating influence of the combination of antioxidants + ion-exchange sorbent on the state of the reserve total bactericidal activity of leukocytes.

In the dynamics of the irreversible stage of chronic obstructive pulmonary disease, in the group of patients receiving antioxidants + sorbent "Lithovit," a more significant and sustained decrease in the level of malondialdehyde and an increase in antioxidant activity of blood were discovered, which testifies to the stabilization of the balance in the system "oxidants-antioxidants."

For the first time, it has been shown that the addition of antioxidants to baseline therapy in combination with the ion-exchange sorbent "Lithovit" leads to a reduction in the number of exacerbations, prolongation of disease remission, a decrease in the rate of progression of chronic airflow limitation and pulmonary hypertension, which leads to an improvement in the quality of life of patients.

Practical Significance

A complex assessment of the expression of oxidative stress and the total bactericidal activity of leukocytes in patients with the irreversible stage of chronic obstructive pulmonary disease has been developed. The assessment of indicators characterizing the balance of pro- and antioxidant activity in the dynamics of the study allows for an objective assessment of disease severity and the forecasting of the character of its course.

Schemes of antioxidant correction for patients with the irreversible stage of chronic obstructive pulmonary disease have been developed, including antioxidants: alpha-tocopherol, ascorbic acid, and a sorbent with ion-exchange properties "Lithovit."

The results of the study are used in the lecture course of the departments of pathophysiology and outpatient therapy at the Novosibirsk State Medical Academy, and in the practical activities of the department of emergency therapy of City Clinical Hospital No. 1.

Positions for Defense

1. The irreversible stage of chronic obstructive pulmonary disease is characterized by a general reduction in the bactericidal activity of effector inflammatory cells and a imbalance in the system "oxidants-antioxidants."

2. The inclusion of antioxidants and sorbents with ion-exchange properties in standard therapy of chronic obstructive pulmonary disease increases the functional activity of leukocytes and contributes to the reduction of imbalance in the system "oxidants-antioxidants."

3. Complex therapy of the irreversible stage of chronic obstructive pulmonary disease is accompanied by a reduction in the number of exacerbations, prolongation of remission, and an improvement in the quality of life of patients.