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Despite significant advances in the diagnosis of tuberculosis, the issues of the mechanism of development and treatment of fibrotic manifestations are relevant and take place in the treatment. The aim of the study was to study the content of perlecane and to find out its participation in the remodeling of the extracellular matrix of the organs of mice with tuberculous inflammation and when they were injected with an antitubercular composition. Materials and methods. The experiment was carried out on male mice of the BALB/c line, which were divided into 4 groups of 5 individuals each. All animals, with the exception of intact mice (group 1), were retroorbitally injected with BCG vaccine once (0.5 mg of microbial bodies in 0.2 ml of 0.9% NaCl solution) to simulate a generalized tuberculosis process. After infection 6 mo for 3 mo, group 2 mice were intraperitoneally injected with 50 µl of 0.9% NaCl solution, group 3 - intraperitoneally with 50 µl of liposome-encapsulated dextrazide solution (LEDZ, isoniazid conjugate and oxidized dextran enclosed in liposomes), group 4 - LEDZ solution was inhaled by spraying in the chamber through a nebulizer for 5 min at the rate of 50 µl of solution per animal. After the last administration of the NaCl and LEDZ solution, mice were removed from the experiment, organs were taken, and tissue homogenates were prepared. The content of perlecane, hyaluronan, protein-bound hydroxyproline, tissue metalloproteinase inhibitors (TIMP-1, TIMP-2) and the activity of matrix metalloproteinases (MMP), hyaluronidases, α2-macroglobulin were measured. Results. In all organs of infected mice, the content of perlecan, hyaluronan, protein-bound hydroxyproline, TIMP-1, TIMP-2 was increased, MMP, hyaluronidase, α2-macroglobulin were activated. Regardless of the method of administration of LEDZ, the severity of fibrosis decreased due to a decrease in the content of hyaluronan in all organs and protein-bound hydroxyproline in the lungs. Perlecan with intraperitoneal administration is involved in fibrosis of the spleen, inhalation - reflects the severity of liver fibrosis. Conclusion. Correlations of perlecan with extracellular matrix components reflect participation in the regulation of fibrosis of organs in BCG-induced inflammation.

The liposomal form of isonicotinic acid hydrazide conjugate with oxidized dextran (liposomeencapsulated dextrazide, LEDZ) injected intraperitoneally for 3 months to BALB/c mice with chronic BCG-induced granulomatosis (6 month after infection) down-regulated activities of protease (MMP) and antiprotease (TIMP-1, TIMP-2, α2-macroglobulin) components of the regulation system, which indicates a drop of destructive and inflammatory potential of BCGinduced granulomatosis. The persistent enhanced hyaluronidase activity in the liver and its reduced (normalized to control level) activity in the lungs after administration of LEDZ indicates a greater hydrolysis of hyaluronan in the liver than in the lungs. LEDZ-induced changes in MMP/TIMP system in mouse liver and lungs are characterized with relative elevation of protease activity over that of antiprotease one.

Administration of the liposome-encapsulated dextrazide (LEDZ) to mice 6 months after infection with mycobacterium BCG vaccine for 3 months modulated metabolism of collagens and the intensity of fibrosis of internal organs. In the liver, we observed a redistribution of glycosaminoglycans towards sulfated forms, a decrease in the content of hyaluronan, a change in the ratio of hydroxyproline fractions indicating a decrease in fibrosis via two mechanisms: suppression of synthesis and increased degradation of collagens. In the lungs, administration of LEDZ did not affect the content of sulfated glycosaminoglycans, but significantly reduced the content of hyaluronan, stimulated degradation of collagen, and reduced its synthesis, but these processes were insufficient for significant reduction of fibrotic complications in the lungs. In animals treated with LEDZ, the decrease in collagen synthesis in the liver was 2-fold more pronounced than in the lungs.

The research studied the content of vascular endothelial growth factor A (VEGF-A) in blood plasma and its relationship with the lipid and extracellular matrix metabolism in men aged 19–69 years living and working in the European part of the Arctic zone of the Russian Federation (Russian Arctic). No age specificity was found in the plasma VEGF-A content. A correlation analysis of different age groups found a significant correlation of the VEGF-A level with parameters of the lipid (cholesterol, LDL-C, Apo B, atherogenicity coefficient, Apo B/Apo A1 ratio) and extracellular matrix metabolism (blood TIMP-4, MMP-2, MMP-3, MMP-9, hyaluronan, total and peptide-bound hydroxyproline, glycosaminoglycans). The discovered correlations indicated the formation of relationships between angiogenesis, atherogenesis, and fibrosis at a specific period of the life of northerners in the Russian Arctic.

Examination of collagen turnover in the liver, lungs, and spleen of BALB/c mice revealed the age-related differences in the levels of hydroxyproline and its fractions. The highest level of total hydroxyproline was observed in the lungs and spleen of young (2-month-old) mice. In the liver, this level attained maximum at the age of 6 months at the expense of elevation of protein-bound hydroxyproline relatively its level in 2-month-old mice. At the age of 12 months, the levels of total hydroxyproline in the liver and spleen were lower than in 6-month-old mice. The decrease in the collagen turnover rate in the liver of 12-month-old mice reflected lower levels of hydroxyproline fractions in comparison with the corresponding values in 6-month-old mice. The rates of collagen turnover in organs differed in mice of different ages: it was maximum in the lungs and spleen of young animals and in the liver of middle-aged mice.

The results of correlation analysis between urine level of melatonin metabolite (6-sulfatoxymelatonin, 6-SMT) in urine and indicators of aging, interstitial fibrosis, and the antioxidant defense system in men in the Arctic are presented. A moderate negative correlation was found for 6-SMT with calendar age, biological age, and the p16INK4a, leucocyte molecular marker of aging. A correlation of 6-SMT with fibrosis indices was found. It is manifested by a negative correlation with sulfated glycosaminoglycans in urine, with collagen markers (free hydroxyproline, peptide-bound hydroxyproline, and total hydroxyproline). The age-related decrease in the 6-SMT level may be associated with an age-related increase in interstitial fibrosis in northerners. A medium-strength positive association of 6-SMT with hormones was detected: the levels of free testosterone (r = 0.53, p = 0.0002), total testosterone (r = 0.43, p = 0.003), and cortisol (r = 0.33, p = 0.007). The negative correlations of 6-SMT with the content of ceruloplasmin (r = –0.63, p = 0.001) and SCORE scale (r = –0.52, p = 0.001) indicate an association of melatonin with the antioxidant defense system and the risk of cardiovascular pathology development.

The content of vascular endothelial growth factor-A (VEGF-A) in blood plasma and its relationship with lipid and extracellular matrix metabolism in working-aged men (19-69 years), living and working in the European part of the Arctic zone of the Russian Federation (Russian Arctic), were studied. No age dependence of the plasma VEGF-A content was found. The correlation analysis, performed in different age groups, revealed significant associations of VEGF-A level with lipid parameters (CS, LDL-C, Apo B, atherogenicity coefficient, Apo B /Apo A1 ratio) and extracellular matrix metabolism (blood TIMP-4, MMP-2, MMP-3, MMP-9, hyaluronan, total and peptide-bound hydroxyproline, glycosaminoglycans). The established correlations indicate the formation of relationships between angiogenesis, atherogenesis and fibrosis at a specific period of life of northerners in the Russian Arctic.Изучено содержание васкулоэндотелиального фактора роста А (VEGF-А) в плазме крови и взаимосвязь его с показателями липидного обмена и метаболизма внеклеточного матрикса у мужчин трудоспособного возраста (19–69 лет), живущих и работающих в Европейской части Арктической зоны РФ (АЗРФ). Показано отсутствие возрастных различий в содержании VEGF-А. Проведенный корреляционный анализ в отдельных возрастных группах мужчин выявил значимые коэффициенты корреляции уровня VEGF-А с показателями липидного профиля (холестерин, ХС ЛПНП, Апо В, коэффициент атерогенности, отношение Апо В /Апо А1) и метаболизма внеклеточного матрикса (ТИМП-4, ММП-2, ММП-3, ММП-9, гиалуронан, общий и пептидно-связанный гидроксипролин, гликозаминогликаны). Выявленные корреляции свидетельствуют о формировании определенной взаимосвязи ангиогенеза, атерогенеза и фиброза на конкретном отрезке жизни северян в АЗРФ.

The liposomal form of isonicotinic acid hydrazide conjugate with oxidized dextran (liposomeencapsulated dextrazide, LEDZ) injected intraperitoneally for 3 months to BALB/c mice with chronic BCG-induced granulomatosis (6 month after infection) down-regulated activities of protease (MMP) and antiprotease (TIMP-1, TIMP-2, α2-macroglobulin) components of the regulation system, which indicates a drop of destructive and inflammatory potential of BCGinduced granulomatosis. The persistent enhanced hyaluronidase activity in the liver and its reduced (normalized to control level) activity in the lungs after administration of LEDZ indicates a greater hydrolysis of hyaluronan in the liver than in the lungs. LEDZ-induced changes in MMP/TIMP system in mouse liver and lungs are characterized with relative elevation of protease activity over that of antiprotease one.

Administration of the liposome-encapsulated dextrazide (LEDZ) to mice 6 months after infection with mycobacterium BCG vaccine for 3 months modulated metabolism of collagens and the intensity of fibrosis of internal organs. In the liver, we observed a redistribution of glycosaminoglycans towards sulfated forms, a decrease in the content of hyaluronan, a change in the ratio of hydroxyproline fractions indicating a decrease in fibrosis via two mechanisms: suppression of synthesis and increased degradation of collagens. In the lungs, administration of LEDZ did not affect the content of sulfated glycosaminoglycans, but significantly reduced the content of hyaluronan, stimulated degradation of collagen, and reduced its synthesis, but these processes were insufficient for significant reduction of fibrotic complications in the lungs. In animals treated with LEDZ, the decrease in collagen synthesis in the liver was 2-fold more pronounced than in the lungs.

Correlations between extracellular matrix components in mouse liver revealed the pathogenetically determined dynamic structure of these interrelations (some correlations appeared while others disappeared) at various terms of BCG-induced granulomatosis. The correlations between the studied parameters were strong during the first (postinfection days 3-10) and the second (postinfection days 60-90) periods but became moderate during the third period manifested by chronic inflammation (postinjection day 180). The greatest number of correlations was observed at the beginning of the stabilization period (postinjection day 60). At this period, the content of all structural components of hepatic proteoglycans closely correlated with that of hydroxyproline. These findings attested to systemic changes in metabolism of extracellular matrix components and interrelation between some structural units of proteoglycans in the liver and the components of extracellular matrix in the lungs. The common and typical organ-specific correlations in the liver and lungs suggest the existence of correlations between different organs during progression of BCG-induced granulomatosis.

We analyzed the concentrations of 6-sulfatoxymelatonin (6-SMT) in working-age men (aged 19–69 years) living in the European part of the Arctic zone of Russia. The 6-SMT level in the studied group was similar to that in the control group of men living in Western Siberia. The 6-SMT level decreased with age and reached the minimal values at the age of 40–49 years. In the group aged 60–69 years, there was a tendency to increase; however, the difference was not statistically significant (p > 0.05) as compared with men aged

This work presents the results of the first ever study of the enzymes involved in the regulation of extracellular matrix metabolism in the European part of Russia’s Arctic zone. The content of matrix metalloproteinases (MMP-1, -2, -3, and -9) and tissue inhibitors of matrix metalloproteinases (TIMP-1, -2, and -4) in blood plasma was evaluated in 91 men, residents of the European part of the Russian Arctic (67° N) and 14 men, residents of Western Siberia (55° N). The content of MMP-1 and MMP-9, as well as TIMP-1 and TIMP-4 in the blood plasma was higher in northerners relative to the Western Siberia residents. The age-related dynamics of MMPs and TIMPs in northerners had a multidirectional trend. We observed the maximum content of MMP-1 and MMP-9 in the group of 30–39 year olds; MMP-3, in the group of 40–49 year olds. The content of these enzymes tended to decrease with age. We found the maximum content of TIMP-1 and TIMP-2 in the group of 50–59 year olds; TIMP-4, in the group of 60–69 year olds; whereas we observed the minimum content of these enzymes in the group of young men under 29 years old. The hyaluronidase activity in plasma was minimal in the group of 30–39 year olds; it increased with age, reaching a maximum value in the group of 50–59 year olds. We can assume that the age-related imbalance in the MMP/TIMP system (a decrease in MMP content with age and vice versa, an increase in TIMP content in older age groups) is one of the reasons for the age-related increase in interstitial fibrosis and premature aging of northerners.

The main extracellular matrix (EM) components in Arctic residents were studied. Northerners had increased levels of total glycosaminoglycans, hyaluronan, and collagen IV in plasma and both general and peptide-bound hydroxyproline in urine, which indicates an accelerated metabolism of the main extracellular matrix components as compared with residents of Western Siberia. Age-related remodeling of the extracellular matrix in northerners manifested in the changed ratio and quantity of its main components. Levels of total glycosaminoglycans, hyaluronan, fibronectin, and hydroxyproline and its fractions increased with age while the level of collagen IV changed insignificantly. The average positive correlation between extracellular matrix components and biological age indicators is suggestive of a relationship between these two processes: aging, which is accelerated on the European North, and pathological remodeling of the extracellular matrix, as it is associated with accelerated aging. Changes in local regulation system, including those related to matrix metalloproteinases and their tissue inhibitors, may be one of the reasons for pathological remodeling of extracellular matrix.

We studied the response of the extracellular matrix of the lungs and liver in mice with BCGinduced granulomatosis (3 months) after inhalation and intraperitoneal administration of liposome-encapsulated dextrazide (LEDZ): a conjugate of oxidized dextran (40 kDa) and isonicotinic acid hydrazide (INH). LEDZ inhalation proved to be more effective in reducing fibrosis severity, both in the lungs and liver. However, the mechanisms of the antifibrotic effect were different: increased degradation and reduced collagen synthesis in the lungs and reduced collagen synthesis and collagen degradation in the liver. This suggest that drug administration routes and delivery to the target organs are crucially important in the therapy of tuberculosis. The antifibrotic effect depended on LEDZ administration route and was more potent after LEDZ inhalation.

Remodeling of the extracellular matrix of the liver in mice with BCG-induced granulomatosis after 2-month course of intraperitoneal injections of isonicotinic acid hydrazide, oxidized dextran conjugated with isonicotinic acid hydrazide, dextrazide, and its liposome-encapsulated form manifested in modification of the proteoglycan composition and hydroxyproline fractions associated with changes in hyaluronidase and MMP activities. The antifibrotic effect of dextrazide and its liposome-encapsulated form manifested in reduction of hydroxyproline fractions that reflected the process of collagen synthesis. Administration of isonicotinic acid hydrazide was followed by a decrease in hydroxyproline fractions reflecting collagen synthesis (antifibrotics effect) and degradation (profibrotic effect), which can be explained by its hepatotoxic activity.

Assessment of the quality of life in male inhabitants of the European Russian North revealed decreased indices of the physical health component (the scale of role functioning determined by physical condition) and mental health component (the scales of social-role functioning and role functioning determined by emotional state and mental health) as compared to the inhabitants of Siberia as a control (comparison) group. Men aged under 29 had the highest scores at all scales. The scores decreased with age. The greatest reduction was observed for the scales of general well-being and bodily pain. There was a moderate decrease for the scales of physical functioning, role functioning determined by emotional state, and role functioning determined by physical condition. Quality of life was closely related to the northerners’ self-rated health, pathology index, molecular marker of aging, and biological age. A negative correlation between these values implies deterioration in the physical and mental health with biological age. The quality of life for the northerners also correlated with their hormonal status. There was a relationship between testosterone and three scales of physical health components, i.e., between cortisol and one scale of physical component and between both dehydroepiandrosterone sulfate and insulin and the scales of physical and mental components of health. The effect of various hormones on different age groups of northerners was demonstrated.

Activity of MMP and content of TIMP and some proteoglycan components were measured in the liver, lungs, and spleen of BALB/c mice aging 2, 6, and 12 months. The increase in the content of proteoglycan components in mouse organs was associated with age-related changes in MMP activity and TIMP-1 and TIMP-2 levels. The ratio between MMP activity and content of TIMP-1 and TIMP-2 differed in the studied organs. The levels of TIMP-1 and TIMP-2 in mouse blood serum and their concentration in studied organs changed asynchronously with age. They are important regulators that determine MMP activity in the analyzed age periods in mice, which can be determined as periods of growth, development, and ageing.

The results of the correlation analysis between the metabolite melatonin - 6-sulfatoxymelatonin (6-SMT) in the urine and the indicators of aging, interstitial fibrosis, the system of antioxidant protection in men in the Arctic are presented. Negative correlation of medium strength between 6-SMT with calendar age, biological age and molecular marker of aging p16INK4a in leukocytes was noted. A relationship of 6-SMT to fibrosis indices was found. It manifested itself in a negative correlation with sulfated glycosaminoglycans in the urine, with collagen markers: free hydroxyproline, peptide-linked hydroxyproline, and total hydroxyproline. Age-related decrease in the level of 6-SMT may be associated with an age-related increase in interstitial fibrosis in northerners. A positive correlation of medium strength between 6-SMT and hormones: free testosterone level (r=0,53, p=0,0002), total testosterone (r=0,43, p=0,003) and cortisol (r=0,33, p=0,007) was shown. Negative correlations of 6-SMT with the content of ceruloplasmin (r=-0,63, p=0,001) and SCORE scale (r=-0,52, p=0,001) indicate the relationship between melatonin and the antioxidant defense system and the risk of cardiovascular pathology.The results of the correlation analysis between the metabolite melatonin - 6-sulfatoxymelatonin (6-SMT) in the urine and the indicators of aging, interstitial fibrosis, the system of antioxidant protection in men in the Arctic are presented. Negative correlation of medium strength between 6-SMT with calendar age, biological age and molecular marker of aging p16INK4a in leukocytes was noted. A relationship of 6-SMT to fibrosis indices was found. It manifested itself in a negative correlation with sulfated glycosaminoglycans in the urine, with collagen markers: free hydroxyproline, peptide-linked hydroxyproline, and total hydroxyproline. Age-related decrease in the level of 6-SMT may be associated with an age-related increase in interstitial fibrosis in northerners. A positive correlation of medium strength between 6-SMT and hormones: free testosterone level (r=0,53, p=0,0002), total testosterone (r=0,43, p=0,003) and cortisol (r=0,33, p=0,007) was shown. Negative correlations of 6-SMT with the content of ceruloplasmin (r=-0,63, p=0,001) and SCORE scale (r=-0,52, p=0,001) indicate the relationship between melatonin and the antioxidant defense system and the risk of cardiovascular pathology.Представлены результаты корреляционного анализа между метаболитом мелатонина — 6-сульфатоксимелатонином (6-СОМТ) в моче и показателями старения, интерстициального фиброза, системы антиоксидантной защиты у мужчин в Арктике. Отмечена отрицательная корреляция средней силы между 6-СОМТ с календарным, биологическим возрастом и молекулярным маркером старения p16INK4a в лейкоцитах. Обнаружена взаимосвязь 6-СОМТ с показателями фиброза. Она проявилась в отрицательной корреляции с сульфатированными гликозаминогликанами в моче, с маркерами коллагена — свободным гидроксипролином, пептидно-связанным гидроксипролином и общим гидроксипролином. Возрастное снижение уровня 6-СОМТ может быть сопряжено с возрастным усилением интерстициального фиброза у северян. Выявлена положительная связь средней силы 6-СОМТ с гормонами: уровнем свободного тестостерона (r=0,53, p=0,0002), общего тестостерона (r=0,43, p=0,003) и кортизола (r=0,33, p=0,007). Отрицательные корреляции 6-СОМТ с содержанием церулоплазмина (r=–0,63, p=0,001) и шкалой SCORE (r=–0,52, p=0,001) свидетельствуют о взаимосвязи мелатонина с системой антиоксидантной защиты и риском развития сердечно-сосудистой патологии.

Age-related decrease in blood concentration of testosterone and dehydroepiandrosterone sulfate was found in mining workers living in the European North. The correlation analysis reveals associations of both hormones with biological age and testosterone with plasma lipid profile. The age dependence of cardiovascular risk and the hormonal mechanisms of its development are discussed.

Structure of proteoglycans in the lungs and total glycosaminoglycan content in blood serum were studied on mouse model of BCG-induced granulomatous inflammation in mice (without destructive processes in the lung parenchyma and granulomas). The maximum level of sulfated glycosaminoglycans in the lungs was detected on postinfection day 30 and was related to their involvement in initiation granulomogenesis and development of granulomas. The maximum level of total glycosaminoglycans in mouse serum on postinfection day 90 coincided with minimum level of sulfated glycosaminoglycans in the lungs. This blood/lungs ratio of glycosaminoglycans can be related to the prevalence of low-molecular-weight hyaluronan fragments promoting inflammation and fibrosis in the lungs observed at the end of the experiment (postinfection day 180).

Experiments on the model of mouse BCG-induced granulomatous showed that the content of glycosaminoglycans and proteoglycans in the extracellular matrix of the liver and lungs are changed at the early stages of inflammation (days 3 and 30 postinfection) before cell destruction in the organs begins. This is related to degradation of extracellular matrix structures. Their high content in the blood and interstitium probably contributes to the formation of granulomas, fibroblast proliferation and organ fibrosis. These processes depend on the infection route that determines different conditions for generalization of the inflammation process. Intravenous method of vaccine injection is preferable to use when designing the experiments simulating tuberculosis granulomatosis, especially for the analysis of its early stages.

Correlations between extracellular matrix components in mouse lungs were examined during various terms of BCG-induced granulomatosis (on postinfection days 3, 30, 60, 90, and 180). During the development of pathological process, the revealed dynamic interrelations between structural units of proteoglycans and hydroxyproline weakened. Most correlations were observed on postinfection day 180. They reflect the relationships not only between the structural units of proteoglycans but also between collagens, presumably determining the maximum degree of fibrosis at this period. The established correlations characterize the systemic nature of reactions in extracellular matrix and its versatile implications determined by the processes going on in the organs and tissues during the onset and development of generalized pathology.

The main extracellular matrix components in Arctic residents were studied. Northerners had increased levels of total glycosaminoglycans, hyaluronan, and collagen IV in plasma and both general and peptide-bound hydroxyproline in urine, which indicates an accelerated metabolism of the main extracellular matrix components compared with comparison group (residents of Siberia). Age-related remodeling of extracellular matrix in northerners manifested in changing ratio and quantity of its main components. Levels of total glycosaminoglycans, hyaluronan, fibronectin, hydroxyproline and its fractions increased with age while the level of collagen IV changed insignificantly. Average positive correlation between extracellular matrix components and biological aging indicators is suggestive of relationship between these two processes: aging - which is accelerated in the Arctic and pathological remodeling of extracellular matrix as it is associated with accelerated aging. Changes in local regulation system including those related to matrix metalloproteinases and their tissue inhibitors may be one of the reasons for pathological remodeling of extracellular matrix.Изучены основные компоненты внеклеточного матрикса (ВМ) у жителей Арктики. У северян содержание общих гликозаминогликанов, гиалуронана и коллагена IV типа в плазме крови, а также общего и пептидносвязанного гидроксипролина в моче увеличено, что свидетельствует об ускоренном метаболизме основных компонентов ВМ относительно группы сравнения (жителей Западной Сибири). Возрастсвязанное ремоделирование ВМ у северян проявлялось в изменении соотношения и количества основных его компонентов. С возрастом содержание общих гликозаминогликанов и гиалуронана, фибронектина, гидроксипролина и его фракций увеличивалось, при этом содержание коллагена IV типа существенно не изменялось. Наличие положительной корреляционной связи средней силы между компонентами ВМ и показателями биологического старения свидетельствует о взаимосвязи двух процессов — старения, которое на Европейском Севере ускорено, и патологического ремоделирования ВМ, поскольку последнее связано с ускоренным старением. Одной из причин патологического ремоделирования ВМ может быть изменение в системе локальной регуляции, в частности — матриксные металлопротеиназы и их тканевые ингибиторы.

Assessment of the quality of life for male inhabitants of the Russian European North demonstrated decreased indices of physical health component (the scale of role functioning determined by physical condition) and mental health component (the scales of social functioning and role functioning determined by emotional state and mental health) compared to the inhabitants of Siberia as a comparison group. Men aged up to 29 had the highest values at all scales. The values decreased with age. The most prominent decrease was observed for the scales of general well-being and pain intensity. There was a moderate decrease for the scales of physical functioning, role functioning determined by emotional state, and role functioning determined by physical condition. Quality of life was closely related to self-reported health of northerners, pathological index, molecular marker of aging, and biological age. Negative correlation between these values implies the deterioration of physical and mental health with biological age. The quality of life for northerners also correlated with hormonal status. There was a relationship between testosterone and three scales of physical health components; between cortisol and one scale of physical component; and between both dehydroepiandrosterone sulfate and insulin and the scales of physical and mental components of health. The effect of various hormones on different age groups of northerners was demonstrated.Оценка качества жизни у мужчин Европейского Севера продемонстрировала снижение показателей физического и психологического компонентов здоровья относительно группы сравнения — жителей Сибири. Максимальные значения по всем шкалам были у мужчин в группе до 29 лет, с возрастом они снижались, особенно заметно для шкал общее здоровье и боль. Умеренно снизились значения по шкалам физическое функционирование, ролевое эмоциональное функционирование, и ролевое физическое функционирование. Качество жизни тесно связано с самооценкой здоровья северян, патологическим индексом, молекулярным маркером старения и биологическим возрастом. Отрицательная связь между ними предполагает ухудшение физического и психологического компонентов здоровья с увеличением биологического возраста. Качество жизни северян имеет корреляционную связь с гормональным статусом. Тестостерон связан с тремя шкалами физического компонента здоровья, кортизол — с одной шкалой физического компонента, дегидроэпиандростерона сульфат и инсулин — со шкалами физического и психологического компонентов здоровья. Показано преимущественное влияние отдельных гормонов в разных возрастных группах северян.

The study in mouse model of BCG-induced granulomatous inflammation showed that early pulmonary fibrosis (day 3-30 postinfection) in tuberculous inflammation was primarily determined by increased number of fibroblasts in the lung interstitium and granulomas and enhanced fibroplastic activity. Fibroplastic processes are initiated via an increase in secretory activity of activated granuloma macrophages caused by the persistence of the pathogen in the cells of the mononuclear phagocytic system. The dynamics of hydroxyproline concentration under these conditions is determined by changes in the number and differentiation degree of fibroblasts in granulomas and lung interstitium at various stages of tuberculous inflammation.

In generalized BCG granulomatosis, fibrosis starts early (on day 3) and not only around the granulomas, but also in the organs. The severity of organ fibrosis is apparently determined by the concentration of granulomas, in particular their macrophages inducing proliferation of fibroblasts in organs and granulomas as well as activation of fibrogenesis. On day 30 after infection, the degree of fibrosis in the lungs was by 6 times higher than in the liver. The increase in hydroxyproline concentration in organs in early period of infection was determined by acute stress, while on day 30 it resulted from its enhanced synthesis by granuloma fibroblasts and resident fibroblasts in organs.

Experimental BCG-induced granulomatosis in mice was used to study changes in the dynamics of individual liver proteoglycan components reflecting phasic extracellular matrix remodeling, determined by the host-parasite interaction and associated with granuloma development. In the early BCG-granulomatosis period, the increase in individual proteoglycan components promotes granuloma formation, providing conditions for mycobacteria adhesion to host cells, migration of phagocytic cells from circulation, and cell-cell interaction leading to granuloma development and fibrosis. Later, reduced reserve capacity of the extracellular matrix, development of interstitial fibrosis and granuloma fibrosis can lead to trophic shortage for cells within the granulomas, migration of macrophages out of them, and development of spontaneous necrosis and apoptosis typical of tuberculosis.

Цель. Изучение интенсивности метаболизма коллагена и общей КЛА сыворотки крови у больных СД 1 типа с различными стадиями нефропатии. Материалы и методы. Обследовано 62 больных СД типа 1. В зависимости от наличия и выраженности ДН больные распределены на 3 группы: в 1-ю (ДН0) вошли 20 больных с нормальной экскрецией белка с мочой, во 2-ю ? 24 пациента с микроальбуминурией (ДН1), в 3-ю ? 18 больных с клинически выраженной ДН (ДН2). Обследование включало определение гликемии, гликированного гемоглобина (HbAlc), клубочковой фильтрации по клиренсу эндогенного креатинина, протеинурии стандартным методом. У больных без явной протеинурии исследовалась альбуминурия. Для оценки метаболизма коллагена в утренней порции мочи определяли содержание пептидносвязанного и свободного гидроксипролина. Результаты. У больных СД выявлено достоверное увеличение содержания общего гидроксипролина в моче в сравнении с контрольной группой. Экскреция пептидносвязанного гидроксипролина зависела от стадии нефропатии. У пациентов с нормоальбуминурией показатель достоверно не отличался от контроля, у больных с микроальбуминурией его величина превышала контроль в среднем в 1,8 раза, а у больных с протеинурией ? в 2 раза. Значимой корреляции между КЛА и экскрецией свободного ГП не установлено. Выводы. Полученные данные свидетельствуют о значительной интенсификации обмена коллагена у больных СД 1 типа и позволяют предполагать вклад этих нарушений в развитие нефропатии. Определение экскреции пептидносвязанного гидроксипролина с мочой и общей КЛА сыворотки крови можно использовать для оценки метаболизма коллагена у пациентов с СД. Изменения метаболизма коллагена при СД появляются еще на доклинических стадиях нефропатии, что указывает на необходимость раннего назначения препаратов, препятствующих накоплению коллагена в почках.

The fibronectin, being one of main components of extracellular matrix of myocardium, is involved into post-infarction repair process. However, the role of fibronectin in this process in patients with myocardium infarction in various periods of their life continues to be a controversial issue. To decide this point the study was organized concerning analysis of content of fibronectin in blood serum in 75 males of three different age groups (prior to 49 years, 50-59 years, 60 -69 years). It is demonstrated that in two groups (prior to 49 years and 50-59 years) the maximal content of fibronectin was marked at second phase regarding to data at first and third phase of reparation process. Whereas in patients aged 60-69 years the maximal content of fibronectin was detected at first phase of reparation process regarding to such in patients aged 50-59 years. The lower content of fibronectin was detected in third phase of reparation process regarding to analogous indicator in other two age groups of patients. These dynamics of content of fibronectin in patients of elder age apparently is an evidence of lower reparation potential of extracellular matrix.

Generalized BCG-induced granulomatous was simulated in BALB/c male mice. The number of tuberculous granulomas in the liver and their size as well as the number of hepatocytes showing vacuolar degeneration increased from day 3 to 180 postinfection. Necrotic changes in hepatocytes were most pronounced at the acute phase of inflammation (days 3 to 30). Proliferative processes in the liver parenchyma in the experimental group were less marked than in the control. Increased content of collagen fibers in the liver was determined by excessive collagen synthesis in necrotic areas as well as increased amount of granulomas and fibroblasts. Enhanced proliferative and fibroplastic activity of fibroblasts in granulomas and liver parenchyma was evidently determined by activated granuloma macrophages. These shifts determined changes in the liver content of hydroxyproline during the acute and chronic periods of the disease.

The paper gives the results of a study of the levels of glycosaminoglycans (GAG) and hydroxyproline (HOP) in 87 apparently healthy individuals of both sexes, aged 19 to 60 years. There is a decrease in the levels of GAG, total HOP, and peptide-bound HOP with advanced age. These indices are higher in subjects less than 45 years old than in those over the age. The found age differences are comparable with higher serum hyaluronidase and collagenolytic activities in subjects younger than 45 years than in those over the age 45 years. Collagen metabolism occurs more intensively in young subjects (under 45 years of age) than in old ones (over 45). There are also gender-related differences: the men had higher levels of GAG and peptide-bound HOP and serum hyaluronidase activity than the women, which suggests that the metabolic rates of collagen and proteoglycans are higher. This difference is complimented by the qualitative characteristics of the process: there is a preponderance of the synthesis of collagen over its degradation with the accelerated degradation of proteoglycans in the young men. In Rh-positive subjects, the content of GAG was 22-fold higher than that in Rh-negative ones.

Dynamics of biochemical markers of reparative fibrosis in patients with myocardial infarction (MI) with complicated course did not differ from that in the group of patients without complications. Development of complications was associated with elevation of blood serum content of glucosaminoglycans in phase 3 of reparative fibrosis compared with group of patients without complications. This elevation was significant in the group of patients with rhythm disturbances. Statistically significant increase of total urinal oxyproline was found in patients with cardiac aneurism in phase 1 and in patients with cardiogenic shock in phase 3 of reparative fibrosis. These subject allow to speak about participation of reparative fibrosis in development of complications. Complications of myocardial infarction developed in patients aged 58 years and older.

The content of the major components of the extracellular matrix was studied in 60 patients with spinal osteochondrosis over time during complex rehabilitative therapy including radon-containing mineral baths (before, 7-9 and 14-15 days after treatment). The complex rehabilitative treatment using radon baths in patients with spinal osteochondrosis was shown to result in a reduction in the serum level of glycosaminoglycans (GAG) and total oxyproline by the end of a course of therapy, which suggests the lower rate of destructive processes in the extracellular matrix. The determination of GAG concentrations and oxyproline forms in patients with asteochondrosis may be used to evaluate the efficiency of the treatment performed.

The content of ceruloplasmin was studied in W/SSM rats with hereditary galactosemia. Carbohydrate component constitutes about 40% of the molecule of this antioxidant. The content of ceruloplasmin in 2- and 11-month-old W/SSM rats was elevated compared to the corresponding parameters in Wistar rats.

In animals with SiO(2)-induced inflammation, exposure in radon-containing water promoted normalization of fibronectin content on days 3 and 10 and reduced the content of glycosaminoglycans on days 3 and 20 compared to the corresponding values in intact animals and rats with SiO(2)-induced inflammation not exposed to radon.

The influence of tocopherol (300 mg/day for 7 days) on skin temperature, arterial blood pressure and pulse rate at local cooling of upper limbs (submersion of both hands in water at +10 degrees C for 10 minutes) in volunteers living in Dixon (74 degrees N in the Taimir national region) was investigated. The findings indicate that the intake of tocopherol prevents temperature decrease in response to cold exposure and promotes more effective initial temperature recovery. Under the influence of tocopherol the spastic reactions of microvessels in the skin to cold became milder. In addition the intake of tocopherol prevents undesirable hemodynamic shifts caused by cold exposure.

In order to find a criterion for human cold resistance and adaptability we studied the reaction of hematological indices to acute general cooling of the whole organism (12 degrees C, 1 h) in 60 male volunteers 19-25 years old living in Norilsk (69 degrees N) for about 2 1/2 years. The first group of subjects comprised of cold adapted individuals whose professional activity was associated with 4-5 hrs daily work outdoor in cold environment. The volunteers of the second group regularly worked indoor and are considered a priori cold unadapted. Our results indicate that fetal hemoglobin (HbF) concentration shows the most remarkable reaction to acute cooling in comparison with other parameters studied (erythrocyte count, hematocrit, total hemoglobin level). Cold exposure of unadapted young males was accompanied by a marked increase of HbF concentration in venous blood (from 1.27 +/- 0.13% to 2.04 +/- 0.02%, p less than 0.01), whereas the same procedure in the adapted subjects was followed by practically unchanged HbF levels. These findings lead us to the conclusion, that the change of the HbF level under acute general cooling can be considered a satisfactory criterion of human cold resistance.

The results have been presented of the zymosan (Z) effect mechanism in the reaction of the lipid peroxidation and the parts' separation of the protection antioxidant. The experiments were made on 32 Wistar rats. At the experimental series 25 mg/kg and 100 mg/kg of Z were injected. Control rats were injected with physiological saline alone.

The results have been presented of the zymosan (Z) effect mechanism in the reaction of the lipid peroxidation and the parts' separation of the protection antioxidant. The experiments were made on 32 Wistar rats. At the experimental series 25 mg/kg and 100 mg/kg of Z were injected. Control rats were injected with physiological saline alone.