[The total content and oligomeric transformations of surfactant protein d in bronchoalveolar lavage fluid in bronchial asthma and gastroesophageal reflux disease: the role in deterioration of the immune response].

The study of pathogenesis of bronchial asthma (BA) and gastroesophageal reflux disease (GERD) or their combination showed that the intensity of inflammation and the choice between Thl and Th2 immune responses are determined by macrophages (elements of congenital immunity). Lung surfactant protein D (SP-D) existing in various oligomneric forms (as monomer trimer, dodecamer, multimer) plays an important role in the mechanism of transformation ofalveolar macrophage phenotype. Patients with BA+GERD have higher SP-D level in the bronchoalveolar lavage fluid than those with GERD alone but lower than patients with BA. SP-D dodecamers were found only in BA patients given basaLtherapy with inhaled glucocorticoids (IGC). It suggests that the presence of dodecamers in the lavage fluid may result firom anti-inflammatory action of IGC. They are absent in patients with BA+GERD treated with IGC probably because GERD enhances inflammatoly changes in the lungs of BA patients despite basal therapy These data together with results of experimental acidification of lavage fluid from BA patients give reason to hypothesize that microaspiration of acidic gastric contents frequently associated with GERD is a cause of local decrease of pH in different segments of the bronchial tree triggering two pathogenetic mechanisms: (I) programming proinflammatory MI phenotype of alveolar macrophages, increased production of nitric oxide, nitrosation of SP-D and destruction of its anti-inflammatory multimers ; (b) direct destruction ofSP-D oligomers in the acid medium. Both mechanisms reduce the level of anti-inflammatory SP-D multimers and increase the level ofproinflammatory monomers. Thus, decreased pH in lower airways is a real pathogenetic factor of anti-inflammatory shift in the oligomeric SP-D composition accounting for the inflammatory reaction of lungs in GERD.

[Functional activity of alveolar macrophages in patients with bronchial asthma and gastroesophageal reflux disease].

Combination of bronchial asthma (BA) and gastroesophageal reflux disease (GERD) is a widespread clinical situation. The two pathologies are known to influence each other leading to disturbances in immune responsiveness. We studied phenotypes and phenotypic plasticity of immune cells (alveolar macrophages) in patients with BA and GERD. It was shown that BA and GERD are largely associated with AM of proinflammatory M2 and anti-inflammatory M1 phenotypes respectively. Population of AM with MI phenotype increases in patients having both BA and GERD compared with that in BA alone. In vitro experiments showed that acidic milieu promotes shifting the phenotype toward the predominance of M1, i.e. simulates the situation characteristic of GERD. Combination of BA and GERD narrows the interval within which AM can change MI phenotype (i.e. makes them more "rigid") but broadens the range in which they can change M2 phenotype. Also, GERD promotes the development of morphological rigidity of AM. Patients with BA given steroid therapy undergo inversion of phenotypic plasticity of AM. These data characterize the immunological component of BA and/or GERD pathogenesis. They help to better understand mechanisms of development of broncho-pulmonary pathology in GERD patients and can be used to work out new methods for the treatment of these diseases.

[Phagocytes protection of periodontium and its ways activation].

In the review of the literature modern data on mechanisms phagocytes protection of periodontium, sold monocytes-macrophage system and neutrophil are resulted. The opportunity of programming of a morphological amd functional phenotype of macrophage is analyzed by change of concentration of whey of blood. Data on functioning in gingival sulcus or periodontal pocket << extracellular neutrophil traps>> are resulted. Opportunities to operate by the nonspecific protective answer of fabrics periodontium on microbic aggression are shown.

[Effect of NO-synthesis blockade on the free-radical processes in rats of different genetic strains with acute alloxan diabetes].

Previously, we have shown that nitric oxide (NO) plays an important role in the pathogenesis of alloxan diabetes (ALD). In this study in August rats, with the congenital increased activity of NO, and in Wistar rats was induced ALD (130 mg/kg, p/c) and 15 days after were examined the effects of the NO-blockade synthesis, induced by administration of Nω-nitro-L-arginine (L-NNA) cour- se on the activity of lipid peroxidation (LP), HIF-1α level, the degree of NO-system activation. The activation of iNOS, HIF-1a expression and 3-nitrotyrosine accumulation in liver were more pronounced in August-ALD rats than in Wistar-ALD rats. The level of TBA-active products in the heart and liver was increased in both diabetic groups only in the first 3 days ofALD and then this indicator of LP sharply was decreased as compared with the control. This effect was pronounced more in August rats. The inhibition of NO overproduction reduced significantly the severity of ALD and prevented the activation of LP, iNOS and HIF-1a. Thus, these data suggest, that NO plays an important role in the pathogenesis of ALD and in the regulation of oxygen homeostasis.

[M1 and M2 macrophage phenotypes functional activity as essential components in innate immune response assessment].

Macrophage capacity to phagocytosis and migration activity are crucial components in innate immune response assessment. Differences in functional responses of two macrophage phenotypes were detected. Phagocytic activity of proinflammatory alveolar M1 phenotype in relation to S. aureus is more expressed than of antinflammatory M2 phenotype. Comparative analysis of migration activity showed alternative dependence of migration index on the type of used chemoattractant.

[Hypoxia, inflammation and phenotypic plasticity of macrophages: the central role of HIF-1 and NFkappaB].

Decrease of oxygen concentration, i.e. hypoxia, in organism tissues and cells is an important pathogenetic component in a large number of diseases. In these cases hypoxia is not only an important component of diseases pathogenesis, but can also influence immune reactions determining the outcome of diseases. Thus, concentration of macrophages in hypoxic areas and their reaction to hypoxia are the key moments in understanding the mechanisms of hypoxia influence on immunity. Macrophages are of the utmost importance in the congenital immune startup and define the vector of development of the adaptive response. In this review we present updated data on influence of hypoxia on macrophages phenotype and their plasticity, and we also analyze genetic trait of macrophages reaction to hypoxia. Molecular mechanisms of immune cells reaction on hypoxia and the role of transcription factors, HIF-1 and NF-kappaB, are analyzed. As a whole, it allowed to describe an important biological phenomenon - hypoxia-regulated control of macrophages phenotypic plasticity, and to define ways of search of new effective approaches to the management of diseases with hypoxic disturbances.

[Resistance to acute hypoxia and changes in the phenotype and phenotypic plasticity of macrophages in mice of different genetic strains].

The aim of study was to investigate the effect of hypoxia on the macrophage phenotype and phenotypic plasticity and to determine the resistance to acute hypoxia in C57/BL mice, which have the pro-inflammatory M1 macrophage phenotype, and in BALB/c mice, which have the anti-inflammatory M2 macrophage phenotype. The following results were obtained. 1) The response of macrophages to acute hypoxia has two successive phases, the immediate, anti-inflammatory phase, and the delayed, pro-inflammatory phase. This response was more distinctly inverted in C57/BL6 M1 macrophages than in BALB/c M2 macrophages; 2) the effect of acute hypoxia on macrophage phenotypic plasticity depends on the genetically predetermined, original macrophage phenotype. In this process, a clear regularity was observed: hypoxia increased the capability of macrophages for changing into the pro-inflammatory M1 phenotype, while their capability for changing into the anti-inflammatory M2 phenotype remained virtually unaffected. 3) BALB/c mice were more resistant to acute hypoxia than C57/BL6 mice. Taken together, these data expand our understanding of mechanisms for pathogenetic effects of hypoxia.

[Surfactant protein D--endogenous regulator of inflammation and immune defense].

Surfactant protein D (SP-D) is a component of lung surfactant, the representative of collagen-like lectines (collectines) family. It plays one of the significant roles in innate antibody-independent immune response. Structural features of SP-D, the possibility of its influence on pathogenetic componentes of inflammatory reaction, expression of inflammatory mediators and attainment of necessary balance between control of inflammatory reaction intensity and formation of the proper response to pathogens allow to consider SP-D as a part of innate immune system of the lung and endogenous regulator of inflammatory reactions in the organism.

[Bronchial asthma and gastroesophageal reflux disease: view of the clinician and pathophysiologist].

Combination of bronchial asthma (BA) with gastroesophageal reflux disease (GRD) is now most prevalent among combined pathology of the respiratory and gastrointestinal tracts. Interaction of these diseases is stated basing on clinical picture and pathogenetic aspects of BA development in the presence of GRD and GRD in the presence of BA. Development of combined affection of gastrointestinal and respiratory tracts occurs in secondary immunodeficiency. Main lines of the paradigm of macrophage phenotypes M1/M2 and mechanisms of alternative development of the immune response Th1/Th2 in combination of GRD with BA are presented. Investigation of macrophage functional activity and Th1/ Th2 balance gives ground for development of the method of macrophage phenotype reprogramming which is a promising approach to effective treatment of combined pathology of the respiratory tract and upper gastrointestinal tract including cases resistant to pharmacological treatment.

[Prevention of the brain neurodegeneration in rats with experimental Alzheimer's disease by adaptation to hypoxia].

The study focused on a possibility of preventing brain neurodegeneration by adaptation to intermittent hypoxia (AH) in rats with experimental Alzheimer's disease (AD) modeled by injection of a neurotoxic bert-amyloid peptide fragment (Ab) into n. basalis magnocellularis. AH was produ- ced in an altitude chamber (4.000 m; 4 hours daily; 14 days). The following results were obtained after fifteen days of the Ab injection: (1) AH substantially prevented the memory impairment induced by Ab, which was determined using the conditioned avoidance reflex test; (2) the AH significantly restricted the enhanced oxidative stress, which was determined spectrophotometrically by thiobarbituric acid-reactive substance level in the hippocampus; (3) the AH completely prevented Ab-induced nitric oxide (NO) overproduction in brain, which was measured by tissue level of nitrite and nitrate; (4) pathologically changed and dead neurons (Niessle staining) were absent in the brain cortex of rats exposed to AH before the Ab injection. Therefore AH seems to effectively prevent oxidative and nitrosative stress thereby providing protection of brain against neurodegeneration and preservation of cognitive function in experimental AD.

[Organ specificity in nitric oxide storage in the blood vessel walls during adaptation to hypoxia].

Addition of N-acetylcysteine induced relaxation of the coronary and basilar arteries thus indicating some basilar NO-stores in these vessels. The maximum capacity of the NO-stores was similar in the coronary and the basilar arteries. Following adaptation to hypoxia, however, the depot was much greater in the coronary artery wall. This seems to be connected with different degree of participation of the NO-dependent vasodiatation in implementation of the adaptive response to hypoxia in coronary and cerebral vascular systems.

[Clinical significance of nitric oxide levels in patients with chronic glomerulonephritis].

Nitric oxide (NO) takes an active part in the regulation of the main renal functions, water-salt metabolism, and system arterial pressure. Under pathological conditions, NO plays the leading role in the development and progression of nephrosclerosis. The aim of this study was to evaluate the clinical significance of serum and urine levels of stable NO metabolites in patients with various clinical forms of chronic glomerulonephritis (CGN), as well as CGN patients with chronic renal failure (CRF). Ninety-seven CGN patients, including 56 ones with preserved nitrogen excretion and 41 ones with CRF, were examined. The levels of stable NO metabolites (nitrites and nitrates) in serum and 24-hour urine were measured. The highest serum and urine NO levels were found in patients with nephrotic and hematuric CGN; patients suffering from latent and hypertonic CGN displayed the lowest levels. Patients with CRF had higher serum levels of NO compared with non-CRF patients. A reverse correlation between serum levels of creatinine and NO in patients with CRF was revealed. In CGN patients without CRF, the activity of inflammatory process, observed by high C-reactive protein levels, was associated with elevation of blood and urine levels of NO, while such an association was not found in patients with CRF.

[Stress proteins in Alzheimer's disease].

Alzheimer's disease (AD) progression can be restricted by brain self-defense systems for a long time since the onset. Among these an exclusive role is played by the system of stress proteins, or heat shock proteins. In AD, stress proteins play primarily a neuroprotective role, which is realized through at least 7 mechanisms: 1) restriction of apoptosis; 2) restriction of NO overproduction; 3) disaggregation of extracellular Abeta aggregates; 4) acceleration of Abeta elimination from intercellular space; 5) restriction of tau-protein hyperphosphorylation; 6) protection of neurons from glutamate toxicity; 7) restriction of intracellular Abeta cytotoxicity. Results of studies on protective effects of heat shock proteins in AD allow creation of a new trend in the field of the treatment, related with developing methods of activation of stress protein self-defense system in order to restrict neurodegenerative disorders. The given review presents theoretical and experimental prerequisites for such an approach, and substantiates its possible efficiency.

[Nitric oxide storage in the cardiovascular system]. / Deponirovanie oksida azota v serdechno-sosudistoi sisteme.

Nitric oxide (NO) is a highly reactive substance with short lifetime. In conditions of a living organism NO can be bound by the complexes used for transport and intracellular storage of NO. The main biological forms of NO store include S-nitrosothiols and dinitrosyl iron complexes capable of interconversion. The NO store formed by these complexes in the vascular wall, on the one hand, provides for protection from excessive free NO after its overproduction and, on the other hand, can be an additional NO source when it is deficient. Apparently, the efficiency of NO storage is genetically determined and corresponds to the inherited level of NO production in the organism. Controlled modulation of formation and dissociation of the NO store is a promising trend for further investigation.

[Catecholamines, nitrogen oxide, and resistivity to stressor lesions: effect of adaptation to hypoxia]. / Katekholaminy, oksid azota i ustoichivost' k stressornym povrezhdeniiam: vliianie adaptatsii k gipoksii.

Pronouncement of stress-induced disturbance of searching behaviour (using "open field" test) and stomach ulceration were compared for the first time with activity of the catecholamine system in hypothalamus and striatum and also with activity of the stress-limiting system of nitric oxide (NO) in the rats of two strains August and Wistar, which differ in their resistance against stress-induced cardiovascular disorders. The effect of prior adaptation to hypobaric hypoxia on these disorders was also studied. August rats appeared to be more resistant than Wistar rats against stress-induced disturbance of the searching behaviour and stomach ulceration. Results of measuring the content of catecholamines in brain structures and the content of NO stable metabolites nitrate/nitrite in plasma suggested that these differences could be due to the stress activation of the nigro-striatal dopaminergic system in August rats, which was not observed in Wistar rats, and also to the higher production of NO in August than in Wistar rats. Adaptation to hypoxia considerably restricted these stress disorders in rats of both strains. Importantly, the protective effects were associated with activation of the nigro-striatal dopaminergic system in all the animals. In the result, adapted Wistar rats, as distinct from non-adapted Wistar rats, displayed a stress activation of this system. The protective effects of adaptation were also accompanied by an increased NO synthesis. Taken together, the data suggest an important role of the responsiveness of the brain dopaminergic system and NO system in the mechanism of resistance against stress-induced disturbances.

[Anti-stress effect of nitric oxide]. / Antistressornyi éffekt oksida azota.

Rat strains feature different resistances to stress. The increased production of nitric oxide (NO) in the August strain prevents the appearance of ulcerous lesions of gastric mucosa and behavioral changes induced by restraint stress. Wistar rats feature a lower level of NO production and are more sensitive to restraint stress compared to the August rats according to both the ulcer pathology and behavioral indices. The stress-induced release of catecholamines was reproduced by experimental hyperfunction of the dopaminergic (DA) system induced by the introduction of L-DOPA. Introduction of NO synthase inhibitor N omega-nitro-L-arginine (L-NNA) enhanced the L-DOPA-induced behavioral changes. This effect was more pronounced in the August strain. The introduction of the exogenous NO donor, dinitrosyl iron complexes (DNIC), limited the behavioral disturbances induced by L-DOPA in both rat strains. The protective effect of DNIC in conditions of the DA system hyperfunction is similar to the effect of a D2 blocker sulpiride. Thus, NO has a central antistress effect, apparently, mediated by limiting the release of catecholamines.

[Correction of NO-dependent cardiovascular disorders by adaptation to hypoxia]. / Korrektsiia NO-zavisimykh serdechno-sosudistykh narushenii s pomoshch'iu adaptatsii k gipoksii.

Spontaneously hypertensive rats (SHR-SP) were adapted to intermittent hypobaric hypoxia in an altitude chamber for 40 days. The adaptation to hypoxia prevented an excessive endothelium-dependent relaxation and hypotension characteristic of myocardial infarction. The adaptation also attenuated the increase in blood pressure and prevented impairment of the endothelium-dependent relaxation in SHR-SP. The universal nature of the adaptation allows to use it for correcting many cardiovascular disorders related to diverse alterations of NO metabolism.

[The role of preventing nitric oxide deficiency in the antihypertensive effect of adaptation to hypoxia]. / Rol' preduprezhdeniia defitsita oksida azota v antigipertenzivnom éffekte adaptatsii k gipoksii.

Shortage of endothelial nitric oxide (NO) manifested as decreased daily urinary excretion of nitrate and nitrite as well as attenuated endothelium-dependent relaxation of conduit and resistance vessels progresses with age-related increase of blood pressure (BP) in stroke-prone spontaneously hypertensive rats (SHRSP). Simultaneous NO-dependent suppression of vascular contractions is, apparently, due to the inducible NO synthase activity in vascular smooth muscle specific for spontaneously hypertensive rat. Adaptation of rats to hypobaric hypoxia initiated at early hypertensive stage (at the age of 5-6 weeks) decelerates hypertension progress. The antihypertensive effect of the adaptation was accompanied by stimulation of endothelial NO synthesis and prevention of impaired NO-dependent response in isolated blood vessels. Nitric oxide stores were formed in the vascular wall of SHRSP and WKY rats at the same time. The obtained data indicate a significant role of correction of endothelial NO deficiency in the antihypertensive effect of adaptation to hypoxia.

[The role of stress proteins HSP70 and the adrenergic system in different resistance to myocardial infarction of August and Wistar genetic rat strains]. / Rol' stress-belkov HSP 70 i adrenergicheskoi sistemy v razlichnoi ustoichivosti k infarktu miokarda krys geneticheskikh linii Avgust i Vistar.

A lesser resistance against myocardial infarction (MI) in the Wistar rats as compared with the August rats was found to be combined with a greater stress-response and activation of the heart sympathetic regulation in the former rats. In the Wistar rats and not in August rats, an activation of hypothalamic noradrenaline (NA) system occurs as well as a greater "output" of the NA from sympathetic terminals in the myocardium. Accumulation of the HSP 70 stress-proteins in IM in the myocardium is nearly 2-2.5-fold lesser in the Wistar rats. Thereupon, different resistance against the IM in Wistar and August rats seems to be due to a genetically determine differences in intensity of the stress-response, activation of the heart sympathetic regulation in the IM, and production of the HSP 70 protective stress-proteins in the myocardium.