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Modern studies have shown a high plasticity and phenotypic diversity of neutrophilic granulocytes (NG) provided by different receptors, which are diagnostic markers for the functional capacity of the cell in the course of their activities. We investigated NG from peripheral blood, obtained from healthy people of both sexes aged from 26 to 66 years. Evaluation of the neutrophil membrane receptor expression was carried out by flow cytometry. The relative amount of neutrophilic granulocytes expressing membrane CD62L, CD63, CD66d receptors and the intensity of their expression were determined according to their fluorescence intensities. The surface NG membrane receptors, i.e., CD62L, CD63, CD66d were studied upon the in vitro experimental influence of the following bacterial peptides: N-formyl-methionyl-leucyl-phenylalanine (FMLP, model 1); glucosaminylmuramyldipeptide (GMDP, model 2), and simultaneous incubation of NG blood with fMLP and GMDP (model 3). The in vitro treatment with fMLP in the in vitro model was used to transform the NG phenotype of conventionally healthy subjects, expressing CD62, CD63, CD66d molecules. The treatment caused a significantly decrease in both CD62L and the CD62L expression in relative amounts of neutrophilic granulocytes with a parallel increase of CD63 expression density. The effect of GMDP on the NG phenotype of conditionally healthy subjects did not change the amount of CD62L+NG and CD63+NG, and did not affect CD62L and CD63 expression density on the surface of NG. However, the amount of CD66d+NG was significantly increased with the unchanged expression of CD66d molecules. GMDP introduced together with the bacterial fMLP peptide was shown to neutralize some features of the NG phenotype transformation caused by fMLP, i.e., the amount of CD62L+ NG was restored by 22 % and the CD62L expression density increased significantly. At the same time, GMDP did not correct the negative effect of fMLP upon the number of CD63+NG and CD66d+NG, and on the CD63 and CD66d expression. Simultaneous addition of fMLP and GMDP did significantly increase the amount of CD66d+NG and expression density of CD63 molecules on the CD63+NG membrane as compared to intact NG of conditionally healthy subjects. The obtained data are important in order to justify some new immunotherapeutic strategies aimed at correction of the negatively transformed NG phenotype, which accompanies some infectious and inflammatory diseases of bacterial etiology with atypical clinical course.
Modern studies have shown a high plasticity and phenotypic diversity of neutrophilic granulocytes (NG) provided by different receptors, which are diagnostic markers for the functional capacity of the cell in the course of their activities. We investigated NG from peripheral blood, obtained from healthy people of both sexes aged from 26 to 66 years. Evaluation of the neutrophil membrane receptor expression was carried out by flow cytometry. The relative amount of neutrophilic granulocytes expressing membrane CD62L, CD63, CD66d receptors and the intensity of their expression were determined according to their fluorescence intensities. The surface NG membrane receptors, i.e., CD62L, CD63, CD66d were studied upon the in vitro experimental influence of the following bacterial peptides: N-formyl-methionyl-leucyl-phenylalanine (FMLP, model 1); glucosaminylmuramyldipeptide (GMDP, model 2), and simultaneous incubation of NG blood with fMLP and GMDP (model 3). The in vitro treatment with fMLP in the in vitro model was used to transform the NG phenotype of conventionally healthy subjects, expressing CD62, CD63, CD66d molecules. The treatment caused a significantly decrease in both CD62L and the CD62L expression in relative amounts of neutrophilic granulocytes with a parallel increase of CD63 expression density. The effect of GMDP on the NG phenotype of conditionally healthy subjects did not change the amount of CD62L+NG and CD63+NG, and did not affect CD62L and CD63 expression density on the surface of NG. However, the amount of CD66d+NG was significantly increased with the unchanged expression of CD66d molecules. GMDP introduced together with the bacterial fMLP peptide was shown to neutralize some features of the NG phenotype transformation caused by fMLP, i.e., the amount of CD62L+ NG was restored by 22 % and the CD62L expression density increased significantly. At the same time, GMDP did not correct the negative effect of fMLP upon the number of CD63+NG and CD66d+NG, and on the CD63 and CD66d expression. Simultaneous addition of fMLP and GMDP did significantly increase the amount of CD66d+NG and expression density of CD63 molecules on the CD63+NG membrane as compared to intact NG of conditionally healthy subjects. The obtained data are important in order to justify some new immunotherapeutic strategies aimed at correction of the negatively transformed NG phenotype, which accompanies some infectious and inflammatory diseases of bacterial etiology with atypical clinical course.
The aim of the study was to investigate a dependence of respiratory burst state in neutrophils on activities of their intracellular enzymes in patients with acute destructive pancreatitis (ADP) of different severity. The study included 50 patients with ADP of moderate (17 cases) and severe degree (33 cases). A group of 47 healthy people was examined as controls. The respiratory burst state was examined in neutrophilic granulocytes by means of chemiluminescence assays. A study of NAD(P)-dependent dehydrogenases activity in blood neutrophils was performed using bioluminescent analysis. We have revealed that a decrease in spontaneous and induced synthesis of superoxide radical by neutrophils was detected in ADP patients, independently of the disease severity. Kinetics of primary ROS synthesis was also impaired in patients with severe ADP. In patients with moderate disorder, the level of secondary ROS synthesis by neutrophils proved to be increased, whereas, in cases of severe disease, a disturbed kinetics of secondary ROS synthesis by neutrophils was detected at a resting state, showing increased synthetic level upon additional induction by zymosan. Metabolism of neutrophils in patients with ADP is characterized by activation of plastic processes (due to the products of the pentose phosphate cycle) and aerobic energy (increased substrate flow intensity in the cycle of tricarboxylic acids). However, NADPH neutrophilic pool in patients with moderate disorder could be additionally supported by enzymatic malic enzyme reactions and NADP-dependent glutamate dehydrogenase. Activation of peroxidation events in patients with severe ADP is revealed, which needs NADPH compensation. The state of energy processes in blood neutrophils in patients with ADP is characterized by lacking changes in glycolytic activity, and increased intensity of substrate flux along tricarboxylic acids cycle. Activity of aerobic processes in patients with moderate disease is maintained by the products of amino acid metabolism (via glutamate dehydrogenase), whereas, in severe ADP it may be provided by products of lipid catabolism. Using correlation analysis, a dependence of respiratory burst of neutrophils on the state of their metabolism was studied. We have found that intensity and kinetics of respiratory burst in the neutrophils of controls depends only on the activity of NADP-dependent dehydrogenases. The changes in cellular metabolic activity in the patients with moderate ADP led to disturbances of their regulatory effect upon the state of neutrophil respiratory burst. In patients with severe disorder, the degree a neutrophil respiratory burst is stimulated by reductive amination of α-ketoglutarate, being, however, inhibited by intracellular peroxidation processes.
Acute peritonitis (AP) is among the most frequent and severe conditions in pediatric abdominal surgery. Due to development of antibiotic resistance and increasing number of atypical infectious and inflammatory diseases (IIDs), a lot of specialists suggest combined treatments for these patients which should include not only surgical and etiotropic approaches, as well as therapy aimed at correction of functional defects of immunity. Neutrophilic granulocytes (NGs) reepresent a unique population of cells of primary anti-infectious immune response. Functional NG defects in pediatric AP play a leading role in development, prevalence, severity of peritoneal inflammation, and response to the therapy. Special role is given to functionally significant NG subsets responsible for triggering and implementation of phagocytosis and microbicidal properties of NG in purulent lesions and inflammatory process in children. There is an urgent need for development of new approaches to targeted immunomodulatory therapy in order to correct the NG dysfunction. The aim of the present study was to arrange the programs of immunomodulatory therapy after surgical treatment of immunocompromised children with various forms of acute peritonitis followed by subsequent evaluation of its clinical and immunological efficacy. The study included 12 immunocompromised children aged 5-12 years with different clinical course of acute peritonitis. The study group 1 included patients with local nonrestricted AP; study group 2 involved children with diffuse AP. The comparison groups consisted of 6 children who received standard therapy, i.e., clinical comparison groups 1 and 2, matched for sex, age and diagnosis. A control group consisted of 18 conditionally healthy children at similar age. Clinical examination included collection of the patient’s history, complaints, objective examination and clinical course assessment of the underlying disease. Immunological study included determination of receptor, phagocytic and microbicidal activity of NCs; assessment of NC subpopulations by their numbers and phenotype using flow cytometry, i.e., the cells co-expressing CD64, CD16, CD32, CD11b, with testing density of these membrane receptors by the MFI approach. Targeted immunomodulatory therapy programs were applied for treatment of children with unrestricted local and diffuse AP, taking into account clinical features of AP, as well as changes in number and phenotype of NC subpopulations, and impairment of their effector function. The standards of postsurgical treatment in the children with various forms of AP included different courses of treatment with Imunofan (Hexapeptide – arginyl-alpha-aspartyl-lysyl-valyl-tyrosyl-arginine; HP) using different schedules and duration. We have shown high clinical and immunological efficiency of these therapeutic programs. Thus, reversal of adequate NG functioning was observed, including positive rearrangements of negatively transformed functional NG subpopulations. In this respect, a positive clinical effect was noted in children with atypical AP with various clinical courses, i.e., absence of postsurgical complications, rapid regression of intoxication signs, normalization of body temperature, reduced volume of antibiotic therapy and shorter hospitalization terms.
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