The effects of antiserotonin preparation on the development of the connective tissue in the lungs, reaction of the blood system, and the content of hemopoietic stem cells, committed hemopoietic and stromal precursors in BM, spleen, and peripheral blood were studied on C57Bl/6 mice with experimental toxic lung fibrosis caused by intratracheal administration of bleomycin. It was demonstrated that the antiserotonin drug inhibits the growth of the connective tissue in the lungs and attenuates the course inflammatory process primarily due to inhibition of the granulocytic lineage, which was related to suppression of hemopoietic stem cells. Reduced content of the stromal precursor cells in BM and spleen was noted.

Effects of a sympatholytic drug on bone marrow stromal and hemopoietic precursors were studied on the model of cyclophosphamide-induced myelosuppression. Sympatholytic treatment increased the content of hemopoietic stem cells of different classes in the bone marrow. Selective stimulation of differentiation of polypotent precursors into granulocyte-macrophage precursors was noted. Acceleration of proliferation and maturation of granulocytic precursors was observed at later terms during regeneration of the hemopoietic tissue. The sympatholytic inhibited proliferation of stromal precursors and reduced feeder activity of fibroblasts for granulocyte precursors.

The effect of course treatment with neuroleptic haloperidol on the inflammatory response and state of the connective tissue in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fibrosis induced by intratracheal administration of bleomycin. This neuroleptic decreased the inflammatory response and reduced the growth of the connective tissue in the lungs. The anti-inflammatory effect of haloperidol is related to a decrease in activity of bone marrow hemopoietic stem cells and committed hemopoietic precursors. The antifibrotic effect of this drug is associated with inhibition of mesenchymal precursor cells.

The influence of granulocyte colony-stimulating factor (G-CSF) has been studied on a model of bleomycin-induced pulmonary fibrosis. It is established that G-CSF significantly increases infiltration of alveolar and alveolar duct interstitium by inflammation cells (lymphocytes, neutrophils, plasmocytes) and increases collagen deposition in lung under conditions of bleomycin introduction. Simultaneously with profibrotic and anti-inflammation effects, G-CSF increased the content of granulocyte cells in the bone marrow and peripheral blood, which was related to the stimulation of committed granulocyte precursors in the bone marrow.

Hemopoiesis-stimulating activity of immobilized oligonucleotide preparation was studied on the model of cytostatic myelosuppression induced by injection of cyclophosphamide and 5-fluorouracil. Immobilized oligonucleotides stimulated regeneration of erythro- and granulocytopoiesis in the bone marrow under conditions of cytostatic treatment. The counts of neutrophilic granulocytes and platelets in the peripheral blood increased. The stimulatory effect of the drug was more manifest in animals with active behavior. The mechanism of immobilized oligonucleotide effect was based on stimulation of functional activity of erythroid and granulocytic macrophage precursors.

The effect of a course treatment with a sympatholytic reserpine on the infl ammatory response and connective tissue proliferation in the lungs of C57Bl/6 mice was studied on the model of toxic pulmonary fi brosis induced by intratracheal administration of bleomycin. This sympatholytic reduced infi ltration of the alveolar interstitium and alveolar ducts with infl ammatory cells (lymphocytes, macrophages, neutrophils, and plasma cells) and prevented connective tissue proliferation in the lungs. The anti-infl ammatory effect of reserpine was associated with a decrease in activity of bone marrow granulocyte-erythroid-macrophage-megakaryocyte and granulocyte precursors (proliferation and mobilization). The antifi brotic effect of reserpine was due to a decrease in the number of committed precursors for mesenchymopoiesis.

The hemopoiesis-stimulating effect of combined treatment with immobilized oligonucleotides and hyaluronidase preparations was studied during cytostatic-induced myelosuppression caused by cyclophosphamide administration. Immobilized hyaluronidase was shown to increase the efficiency of correction of changes in the erythroid and granulocytic hemopoietic stems with immobilized oligonucleotides. This potentiation of the effect of immobilized oligonucleotides by immobilized hyaluronidase was related to an increase in functional activity of committed hemopoietic precursors.

The effects of immobilized granulocyte colony-stimulating factor (mediated by cells of the hemopoiesis-inducing microenvironment) on hemopoietic precursors of various classes were studied on the model of cytostatic-induced myelosuppression (administration of cyclophosphamide). The action of this preparation was compared with that of the standard preparation of granulocyte colony-stimulating factor. Thy 1,2+ cells potentiated the effects of immobilized and standard granulocyte colony-stimulating factors on granulocyte-erythroid-macrophagemegakaryocyte precursors. Stromal cells were shown to potentiate the influence of these agents on granulocyte precursors. Induction of proliferation of precursor cells by the immobilized factor mediated by cells of the hemopoiesis-inducing microenvironment persisted for a longer period compared to that induced by the standard product.

On the model of toxic diffuse pulmonary fibrosis induced by intratracheal administration of bleomycin, we studied reactions of the blood system, content of stem cells, committed hemopoietic and stromal progenitor cells in the bone marrow, spleen and peripheral blood of C57Bl/6 mice. It was shown that the development of diffuse pulmonary fibrosis was accompanied by hyperplasia of bone marrow hemopoiesis and leukocytosis in the peripheral blood. Activation of the erythroid and granulocytic hemopoietic stems was related to stimulation of hemopoietic stem cells (polypotent cells, granulocyte/erythroid/macrophage/megakaryocyte precursor cells) and committed erythroid and myeloid progenitor cells in the bone marrow. At the same time, the number of stromal precursors increased. Bleomycin increased the count of hemopoietic stem cells the peripheral blood and spleen and reduced the content of mesenchymal stem cells in the spleen and bone marrow.

Experiments were performed on the model of cyclophosphamide-induced myelosuppression. We showed that regeneration of the granulocytic hemopoietic stem is related to activation of multipotent, granulocyte-erythroid-macrophage-megakaryocyte, and granulocyte-macrophage precursors. The division and maturation of granulocyte colony-forming cells and significant decrease in the number of these cells in the bone were suppressed under these conditions. The granulocytopoiesis-stimulating effect of granulocyte CSF during myelosuppression was associated with an increase in functional activity of multipotent and granulocyte-erythroidmacrophage-megakaryocyte precursors (primarily of differentiation). In the period of regeneration, this effect was attributed to activity of granulocyte precursors.

Experiments were performed on the model of cytostatic myelosuppression induced by cyclophosphamide. We compared the effect of immobilized granulocyte CSF (the preparation was created in Russia) and reference standard preparation of granulocyte CSF on the development of neutrophilic leukopenia and hemopoietic precursors of various classes. It was found that preparations of granulocyte CSF decreased the duration and degree of peripheral blood neutropenia. The granulocytopoiesis-stimulating effect was related to stimulation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage-megakaryocyte precursors, and granulocyte precursors. Induction of division and maturation of multipotent hemopoietic precursors, granulocyte-erythroid-macrophage-megakaryocyte precursors, and granulocyte precursors and recovery of cellularity of the granulocytic hemopoietic stem after administration of immobilized granulocyte CSF were observed at later terms compared to treatment with the reference preparation of granulocyte CSF.

Предложена новая модель изучения процессов миграции циркулирующих в периферической крови стволовых клеток. Исследована мобилизующая предшественники активность гранулоцитарного колониестимулирующего фактора (Г-КСФ), иммобилизированного (имм) на полиэтиленоксиде с помощью нанотехнологии электронно-лучевого синтеза. Выявлена выраженная способность иммГ-КСФ вызывать выход в кровь костномозговых мезенхимальных и кроветворных прогениторных клеток различной степени зрелости. Установлено, что иммГ-КСФ по своей активности превосходит действие неконъюгированного Г-КСФ. Показано наличие специфической активности иммГ-КСФ при его приеме внутрь.

Effect of the antiserotonin drug cyproheptadine on the erythropoiesis has been studied under conditions of the administration of cytostatics (fluoropyrimidine antimetabolite 5-fluorouracil (5-FU), alkylating agent cyclophosphane) with different mechanisms of action. It is established that the antiserotonin drug significantly accelerates regeneration of the erythroid hemopoietic branch, especially in the case of 5-FU. The depression of erythron under the conditions of cyclophosphane injections was retained. The erythropoiesis-stimulating effect of cyproheptadine is based on the restoration of the structural and functional organization of the bone marrow (formation of erythroid hemopoietic islets).

Effects of serotonin and adrenomimetics (phenylephrine and isoprenaline) on bone marrow stromal and polypotent hemopoietic precursors were studied in vitro on the model of cyclophosphamide-induced myelosuppression. It was found that under conditions of myelosuppression, adrenomimetics potentiate differentiation of polypotent hemopoietic precursors into mature precursors (granulocyte-macrophage and granulocyte CFU) initiated by granulocytic CSF, while serotonin suppresses these processes. Adrenomimetics (especially, isoprenaline) abolish high rate of division of stromal precursors and suppress the growth of granulocytic CSF induced by fibroblast-like cells. Serotonin does not affect proliferation of stromal precursors, but potentiates the granulocytopoiesis-stimulating effects of fibroblasts.

Neuroprotective activity of immobilized granulocyte CSF (nanotechnology with electronbeam synthesis) and hyaluronidase was studied on the model of posthypoxic encephalopathy. Oral administration of immobilized granulocyte CSF had no effect on manifestations of posthypoxic psychoneurological disorders in animals. Combined treatment with immobilized granulocyte CSF and hyaluronidase prevented impairment of orientation and exploratory behavior and development of amnesia in mice with hypoxic injury.

This study demonstrated the possibility of in vivo activation of progenitor cells by hyaluronidase. Specifically, treatment with hyaluronidase increased the number of mesenchymal and bone marrow precursor cells, their proliferative activity, and differentiation. Also, it promoted stem cell mobilization into blood under effect of granulocyte colony-stimulating factor (G-CSF) and enhanced progenitor cell adhesive properties. Therapeutic efficiency of transplantation of mononuclear cells isolated from peripheral blood after administration of G-CSF improved under effect of hyaluronidase. Hyaluronidase immobilized by electron beam synthesis nanotechnology exhibited high specific activity with respect to stem cells via both enteral and parenteral routes.