Results and Prospects of Using Activator of Hematopoietic Stem Cell Differentiation in Complex Therapy for Patients with COVID-19.

The paper presents the results of a standard and complex treatment method using the peptide drug thymus thymalin in patients with COVID-19. One of the mechanisms of the immunomodulatory effect of thymalin is considered to be the ability of this peptide drug to influence the differentiation of human hematopoietic stem cells (HSCs). It was found that, as a result of standard treatment, patients in the control group showed a decrease in the concentration of the pro-inflammatory cytokine IL-6, C-reactive protein, D-dimer. The addition of thymalin to standard therapy accelerated the decline in both these indicators and the indicators of the T cell system. This has helped reduce the risk of blood clots in COVID-19 patients. The revealed properties of the thymus peptide preparation are the rationale for its inclusion in the complex treatment of coronavirus infection. Peptideswith potential biological activity against SARS-CoV-2 virus [29]. Note: Nitrogen atoms are shown in blue, oxygen atoms - in red, carbon atoms - in gray, hydrogen atoms - in white, and phosphorus atoms - in yellow.

[The concept of chronic obstructive pulmonary disease clinical control as a decision - making tool in real clinical practice for optimizing of basic pharmacotherapy].

The main goals of COPD therapy are to achieve clinical stability with minimal clinical manifestations and low risk of relapse. The proposed COPD control concept by analogy with asthma has not been quite well characterized yet. COPD control is defined as "the long - term maintenance of a clinical situation with a low impact of symptoms on the patient's life and absence of exacerbations." The situation of clinical control in COPD is considered desirable and potentially achievable for most patients with COPD. Pharmacotherapeutic options for COPD are constantly expanding. The control concept may be useful when the decision on treatment of COPD is made for dynamic adjustment of the therapy volume.

[Features of central hemodynamics in patients with community - acquired pneumonia depending on the course of the disease and cardiovascular comorbidity].

AIM: The study of intracardiac hemodynamics and blood flow in the pulmonary circuit in patients with community - acquired pneumonia, depending on the presence of concomitant pathology of the cardiovascular system and the severity of the pathological process. MATERIALS AND METHODS: In 43 patients with community - acquired pneumonia (22 men, 21 women, mean age 67±17 years), the functional state of pulmonary - cardiac hemodynamics was assessed by echodoplerography. All subjects were divided into 2 groups: 1st group - 25 patients with community - acquired pneumonia (mean age 49±18 years) without concomitant pathology of the cardiovascular system and 2nd group - 18 patients with community - acquired pneumonia (mean age 70.1±11 years) with concomitant cardiovascular disease. RESULTS: The main ultrasound parameters did not differ from the normal values in patients from the 1st group. In patients from the 2nd group there was a significant deterioration of several pulmonary - cardiac hemodynamics parameters, decrease of left ventricular ejection fraction, significant myocardial hypertrophy of the left ventricle and left atrium size increase. Regarding the right heart chambers it was revealed dilatation of the right ventricle, increasing of the estimated systolic pressure in the right ventricle, deterioration of right ventricle myocardial diastolic function, increase of the: RV/LV size ratio, LV eccentricity index, RV myocardium thickness, diameter of the pulmonary artery, velocity of pulmonary regurgitation and the area right atrium size. In addition, the amplitude of systolic displacement of the tricuspid valve ring and the intensity of inspiratory collapse of the inferior vena cava decreased. Correlation analysis of clinical and laboratory parameters, which are markers of endogenous intoxication, oxygen saturation of arterial blood (SpO2), separately for two groups of patients with community - acquired pneumonia, showed a reliable correlation with a number of informative and used in the practice echocardiography parameters of pulmonary cardiac hemodynamics, characterizing systolic (systolic movement amplitude of the tricuspid valve ring - TAPSE), as well as diastolic function (E/A of the right ventricle) of the heart. CONCLUSION: The relationship between the severity of pulmonary - cardiac hemodynamics disturbances in patients with community - acquired pneumonia, having comorbid pathology, contributing to the deterioration of pulmonary - cardiac hemodynamics and more severe course of the disease with markers of the inflammatory process and oxygen saturation of arterial blood decrease is revealed.

Efficacy of Arbidol in the prevention of virus-induced exacerbations of bronchial asthma and chronic obstructive pulmonary disease.

AIM: To assess the efficacy and safety of Arbidol in the influenza and ARVI preventing in patients with asthma and chronic obstructive pulmonary disease (COPD). MATERIALS AND METHODS: This study was an open label and prospective during epidemic period of 2016-2017 years. 100 outpatients aged 18 to 80 years with verified asthma and/or COPD, were enrolled to therapy group, and received oral umifenovir 200 mg once daily for 14 days and then 200 mg twice a week for 3 weeks.The medical records data for the same epidemic period of 2016-2017 seasons of the same patients during witch they received no prophylaxis was taken as a control. The data analysis was made by applying parametric and nonparametric statistical methods. RESULTS: Seasonal and post-exposure prophylaxis using umifenovir was associated with 2.6-times reduction in influenza and ARVI morbidity compared to control. In diseased patients (ARVI) of the therapy group the number of patients with mild illness prevailed (62.2%) and was significantly differed from control (37.1%). Severity of catarrhal symptoms and intoxication, was reduced with umifenovir prophylaxis course and were mild in 67.6% and 67.6% respectively of therapy group compared with 43.3% and 46.4% of control. Influenza and ARVI complications were only detected in control group (4 cases). The percentage of patients with incidents of underlying disease exacerbation was 42% in therapy group and 93% in control group. Also, exacerbation in the therapy group were mild in 59.5% and 34.4% in control group, while moderate exacerbation prevailed in control group and was in 59.1% of cases with was significantly higher then in therapy group (39.3%). Results in more frequent use of adjuvant in the control group compared with the therapy group (81.7% and 59.5% respectively). Patients of control group had a higher risk of hospitalizations due to underlying disease aggravation (11.8%), compared with therapy group (9.5%) but these differences were not significant. CONCLUSION: Seasonal and post-exposure prophylaxis with Arbidol reduce influenza and ARVI morbidity in patients with asthma and COPD during epidemic period, frequency and severity of chronic obstructive pulmonary disease aggravations resulting in decrease in the number of hospitalizations. Also, prophylaxis with Arbidol reduced the severity of catarrhal symptoms and intoxication.

[ROLE OF MAST CELLS IN BRONCHIAL CONTRACTION IN NONALLERGIC OBSTRUCTIVE LUNG PATHOLOGY].

In model of chronic obstructive pulmonary disease induced in rats by 60-day intermittent exposure to nitrogen dioxide mast cells participation in the mechanism of bronchial smooth muscle contractile activity patterns was evaluated. Since the 31st day, one group of rats was inhaled with sodium cromoglycate every day before the nitrogen dioxide exposure to stabilize the mast cell membrane. The other group (control) hasn't been treated. Isometric contraction of the bronchial isolated preparations in response to nerve or smooth muscle stimulation were determined. Inhibition of mast cell degranulation and the release of endogenous histamine by stabilizing cell membranes prevented the development of bronchial smooth muscle hyperactivity caused by prolonged inhalation of nitrogen dioxide. It is believed that a mechanism to increase the contractile activity of the bronchial wall smooth muscles is mediated by activation of the transmembrane adenosine receptor in resident mast cells, leading to their partial degranulation with release of histamine, acting on the histamine Hl-receptors with the launch of reflex pathways through intramural ganglion neurons.

[ANTIINFLAMMATORY AND REGENERATIVE EFFECT OF PEPTIDE THERAPY IN THE MODEL OF OBSTRUCTIVE LUNG PATHOLOGY].

The effect of the tetrapeptide bronchogen on the structural and functional state of the bronchial epithelium and inflammatory activity in the lungs was studied in the chronic obstructive pulmonary disease (COPD) model, created in rats by a 60-day intermittent exposure to nitrogen dioxide. The cell composition and cytokine-enzyme profile of bronchoalveolar lavage fluid (BALF), the content of secretory immunoglobulin A and surfactant protein B in BALF were determined. Following the course of peptide treatment the decreased activity of neutrophilic inflammation with the normalization of cellular composition and profile of pro-inflammatory cytokines and enzymes in the bronchoalveolar space was observed. The structure of bronchial epithelium, disturbed during formation of COPD model, was restored and accompanied by restoration of its functional activity as evidenced by an increase of secretory immunoglobulin A (local immunity marker) and surfactant protein B, responsible for reducing the alveolar surface tension.

The Diagnostic Value of Alpha-1-Antitrypsin Phenotype in Patients with Granulomatosis with Polyangiitis.

The deficiency of alpha-1 protease inhibitor, or alpha-1-antitrypsin (A1AT), predisposes to chronic lung diseases and extrapulmonary pathology. Besides classical manifestations, such as pulmonary emphysema and liver disease, alpha-1-antitrypsin deficiency (A1ATD) is also known to be associated with granulomatosis with polyangiitis (GPA or Wegener's granulomatosis). The aim of our study was to evaluate the frequency of allelic isoforms of A1AT and their clinical significance among GPA patients. Detailed clinical information, including Birmingham Vasculitis Activity Score (BVAS), incidence of lung involvement, anti-proteinase 3 (PR3) antibodies concentrations, and other laboratory data were collected in 38 GPA patients. We also studied serum samples obtained from 46 healthy donors. In all collected samples A1AT phenotyping by isoelectrofocusing (IEF) and turbidimetric A1AT measurement were performed. Abnormal A1AT variants were found in 18.4% (7/38) of cases: 1 ZZ, 4 MZ, 2 MF, and only 1 MZ in control group (2%). The mean A1AT concentration in samples with atypical A1AT phenotypes was significantly lower (P = 0.0038) than in normal A1AT phenotype. We found that patients with abnormal A1AT phenotypes had significantly higher vasculitis activity (BVAS) as well as anti-PR3 antibodies concentration. We conclude that A1AT deficiency should be considered in all patients with GPA.

[EFFECT OF MAST CELL DEGRANULATION BLOCKADE ON THE INFLAMMATION OUTCOME IN THE MODEL OF OBSTRUCTIVE LUNG PATHOLOGY].

Effect of mast cell degranulation blockade on the inflammatory response and character of the lung tissue structure-functional changes were evaluated in the chronic obstructive pulmonary disease model produced in rats by 60-day intermittent exposure to nitrogen dioxide. The membrane stabilizer sodium cromoglicate was used to blockade of mast cell degranulation. Lung tissue sections were stained with toluidine blue to identify mast cells. Bronchoalveolar lavage fluid (BALF) cytogram was determined. The levels of mast cell tryptase and chymase, proinflammatory cytokine TNF-α, surfactant protein B were measured in BALF. Suppression of mast cell degranulation prevented the release of proteases in the bronchoalveolar space and reduced activity of the inflammatory process. The influx of inflammatory cells and TNF-α concentration decreased. There was no interstitial inflammatory infiltration. Bronchoalveolar epithelium structure was recovered that is the basis of its functional usefulness. The results confirm the active involvement of mast cells in the development of the inflammatory process in obstructive pulmonary diseases and allow us to consider them as a possible therapeutic target.

[ENDOTHELIAL DYSFUNCTION AND OBSTRUCTIVE LUNG PATHOLOGY].

Relationship of endothelial dysfunction and obstructive pulmonary diseases is a complex and poorly understood. Vascular endothelium is a multifunctional autonomous endocrine organ. The review discusses the various functions of the endothelium, causes, mechanisms and possible markers of endothelial dysfunction. The contribution of pulmonary vessel endothelial dysfunction in the initiation and progression of chronic obstructive pulmonary disease and asthma is considered. The existing approaches to the restoration of the structural and functional integrity of the vascular endothelium are discussed.

Modulating Effect of Peptide Therapy on the Morphofunctional State of Bronchial Epithelium in Rats with Obstructive Lung Pathology.

On the model of chronic obstructive pulmonary disease, the effect of therapy with low-molecular-weight peptides on restructuring and functional activity of bronchial epithelium for restoring the immune and barrier function of the lungs and prevention of inflammatory process progression was studied. Chronic obstructive pulmonary disease was modeled in rats by 60-day intermittent exposure to NO2. Administration of tetrapeptide Bronchogen for 1 month eliminates symptoms of remodeling of the bronchial epithelium and lung tissue typical of chronic obstructive pulmonary disease (goblet cell hyperplasia, squamous metaplasia, lymphocytic infiltration and emphysema, and restoration of ciliated cells). Enhanced production of secretory IgA, a local immunity marker, attested to normalization of functional activity of bronchial epithelium, while normalization of cell composition and profile of proinflammatory cytokines in the bronchoalveolar space reflected reduction of neutrophilic inflammation.

[MODIFICATION OF ALVEOLAR MACROPHAGE POOL UNDER INFLUENCE OF PEPTIDE THERAPY IN THE BLEOMYCIN PNEUMOFIBROSIS MODEL].

Effect of peptide therapy on morphological and functional characteristics of alveolar macrophages and role of their phenotypic reprogramming in modulation of pulmonary fibrosing process were evaluated on the rat's model of pulmonary fibrosis, initiated by intratracheal administration of bleomycin. Status of alveolar macrophages was evaluated on the basis of electron microscopic studies and phagocytic activity. In lung tissue of control animals widespread diffuse interstitial fibrosis was determined. Alveolar macrophage cytoplasm was filled geterophagosomes with surfactant fragments, lipid droplets and cholesterol crystals; foam cells were a third of macrophage pool. After the course of peptide therapy the young cell with rare geterophagosomes and lipid droplets, without cholesterol crystals and increased phagocytic activity prevailed in macrophage population. There were rare sites of fibrosis in lungs; connective tissue contained much less collagen fibers than in the control; there was a growing proliferation of the bronchial epithelium. It may be assumed that under the influence of the peptide therapy a certain balance in the alveolar macrophage population was established with a predominance of M2 phenotype for the formation of the optimal ratio of cellular and humoral immune response, providing effective remedy of bronchial epithelium and prevention of lung tissue remodeling with the interstitial fibrosis formation.

[Effect of endotelioprotectors on the tone of pulmonary arteries and bronchi in the model of obstructive lung pathology].

In the model of chronic obstructive pulmonary disease (COPD), produced in rats by 60-day exposure to nitrogen dioxide, the effect of drugs with endotelioprotector properties (sulodexide and rosuvastatin) on the functional state of small pulmonary arteries and bronchi was studied. We evaluated the contractile activity of smooth muscle strips of the bronchi caused by stimulation of the nerves or muscles, and changes in tone of isolated pulmonary artery rings at the application of reagents-vasodilators. The use of sulodexide promoted restoration NO-dependent mechanism of vasodilatation and improved ß-adrenergic regulation of the pulmonary artery tone. The use of rosuvastatin had no effect on the dilator activity of pulmonary arteries. Both drugs improved the functional status of the bronchial smooth muscles and intrabronchial nervous system that controls the contractile activity of smooth muscle structures of the airways. The results of the study suggest that the one-way relaxing effect of sulodexide on pulmonary arterial and bronchial smooth muscles enables the recovery of coordinated regulation of the tone of these structures, which is essential for maintaining the optimal ratio of ventilation and pulmonary blood flow for efficient gas exchange.

[Cell-molecular mechanisms of nitrogen dioxide-induced damaging effect on bronchial epithelium].

Nitrogen dioxide and reactive nitrogen species play a key role in the development environment related diseases by initiation of cell death and damage of bronchoalveolar epithelium. This review examines the possible cell-molecular mechanisms of nitrogen dioxide-induced damaging effect on bronchial epithelium.

Protective effect of fenspiride on the bronchi in rats with chronic obstructive pulmonary disease.

We studied the effect of a non-steroidal anti-inflammatory drug fenspiride on contractive activity of bronchial smooth muscles on the model of chronic obstructive pulmonary disease of rats induced by 60-day exposure to nitrogen dioxide. The administration of fenspiride during the acute stage of the disease (day 15) abolished the constricting effect of the pollutant on the bronchial smooth muscles. Dilatation effect of fenspiride in a low dose (0.15 mg/kg) was mediated by its interaction with nerve endings of bronchial capsaicin-sensitive nerve C-fibers. The interaction of drug with receptors of C-fibers prevented neurogenic inflammation, which was confirmed by the absence of structural changes in the lungs typical of this pathology. The broncholytic effect of fenspiride in a high dose (15 mg/kg) was mediated by not only afferent pathways, but also its direct relaxing action on smooth muscle cells. The observed anti-inflammatory and bronchodilatation effect of fenspiride in very low doses can be used for prevention of chronic obstructive pulmonary disease in risk-group patients contacting with aggressive environmental factors.

Experimental modelling of chronic obstructive pulmonary disease.

A method for experimental reproduction of stages of chronic obstructive pulmonary disease formation (from acute inflammation to bronchopulmonary tissue restructuring characteristic of this disease) is presented. Lung injury and inflammation were induced by nitrogen dioxide. Hyperplasia and hypersecretion of goblet cells, squamous cell metaplasia of the ciliary epithelium, emphysema, and focal fibrosis served as the morphological substrate for the formation of bronchial obstruction. The adequacy of the model is confirmed by signs characteristic of chronic obstructive pulmonary disease: hyperexpression of CD3 lymphocytes in the bronchial wall and parenchyma, manifold increased production of TNFα and TGFß, high concentrations of circulating pathogenic immune complexes. Persistence of the structural and functional shifts throughout 6 months after exposure to nitrogen dioxide indicated a chronic course of the resultant pathological process.

[Effect of tiotropium bromide on exercise tolerance in patients with chronic obstructive pulmonary disease].

This open prospective randomized parallel-group comparative study included 43 patients with moderate or severe chronic obstructive pulmonary disease (COPD). The patients of active working age were referred to the disability groups II-III based on the average forced expiratory volume in 1 second (1.70+/0.43 1 or 49.1+/-10.7% the normal value) and received an eight-week course of pulmonary rehabilitation. During the study, the patients were given tiotropium bromide (TB) for 14 weeks to assess its effect on the tolerance of physical activity. A combination of TB with pulmonary rehabilitation was shown to improve tolerance evaluated by whole-body rheography (WBR) in a 6 minute step-test and the standard functional test. Also, this treatment resulted in the clinically significant alleviation of dyspnea and permitted to decrease the intake of salbutamol (used "as required") compared with pulmonary rehabilitation alone. It is concluded that combination of TB and pulmonary rehabilitation provides an effective tool for the treatment of patients with COPD. The whole-body rheographic technique can be used to evaluate the functional state of the patients and the efficiency of their rehabilitation.

[Combination of thiotropium bromide with almitrine and pulmonary rehabilitation in the treatment of patients with chronic obstructive pulmonary disease].

AIM: To elucidate efficacy of a combination almitrine+thiotropium bromide (TB)+pulmonary rehabilitation (PR) in chronic obstructive pulmonary disease (COPD) of stage II-III complicated with chronic respiratory failure (CRF). MATERIAL AND METHODS: Efficacy of therapy was compared in two groups of patients: group 1 (n = 22) received TB in a dose 18 mcg/day for one year, almitrine in a dose 10 mg/kg/day for 3 months, an 8 week course of PR, group 2 (n = 17) received TB and PR. The treatment efficacy was determined by spirometric parameters of external respiration function, blood gases, dyspnea indices, exercise tolerance assessed by 6-min walk test, quality of life (St. George Hospital Respiratory Questionnaire). RESULTS: Group 1 patients walked longer distance after a course of PR and 1 year later (by 90.5 +/- 25.4 and 44.5 +/- 10.2 m, respectively, p < 0.05), had reduced desaturation measured by pulsoxym-etry at the end of 6-min walk test, increased PaO2 in baseline under 70 mmHg (by 5.8 +/- 1.2 mmHg, p > 0.05), decreased exacerbation rate per 1 patient a year (by 25%). CONCLUSION: Combination treatment with TB, almitrine and PR is indicated for COPD patients with moderate hypoxemia.

[Jet transcatheter artificial ventilation in the surgical treatment of tracheal cicatricial stenosis].

The authors present the results of a study of the baseline condition, the parameters of external respiratory function, gas exchange, and hemodynamics in 42 patients with tracheal cicatricial stenosis (TCS). The impact of transcatheter normofrequency artificial ventilation (AL) on the respiratory and circulatory parameters was studied during surgical TCS removal. The baseline impairments were identified in the external respiratory system and in the hemodynamic provision of breathing processes, which corresponded to first-second grade respiratory failure disorders, despite preoperative tracheal bougienage elimination. Normofrequency and high-frequency AL is the method of choice in treating patients with concomitant respiratory diseases.