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Suppression of the production of granulocytic CSF under the effect of 5-fluorouracyl is related to disorders in the NF-κB-, cAMP-dependent signaling pathways and MAPK cascade. These secondary messengers are involved in the regulation of functional activity of nonadherent myelokaryocytes starting from day 10 of the experiment (initial period of the hemopoietic granulocytic stem regeneration after antimetabolite challenge). Granulocytic CSF does not play essential role in the formation of colony-stimulating activity of cells of the adherent and nonadherent fractions of the bone marrow. Only cAMP-dependent pathway is involved in the regulation of the realization of the granulocytic precursor growth potential in response to the challenge.

The involvement of the studied signal cascades in the regulation of erythropoietin production by bone marrow nuclears under conditions of immobilization stress depends on the type of the hemopoiesis-inducing microenvironment cells and the period of blood system reaction to stress exposure. Secretory activity of monocytes is regulated mainly by PI3K improving cell resistance to disturbances. The functional role of signal cascades involved in the production of erythropoietin by T cells is determined by the stage of the common adaptation syndrome.

Protein kinase p38 was shown to contribute to the increase in production of granulocyte CSF by microenvironmental cells under conditions of restraint stress. Stimulation of colony-forming activity was not accompanied by the increase in maturation of clonogenic structures in the bone marrow granulocytic stem. This process was realized with the involvement of NF-κB-dependent signaling and p38 MAPK signaling pathway. Our study showed that the p38 MAPK signaling pathway plays an important role in the regulation of granulocytopoiesis, but not of erythropoiesis.

We compared hemostimulating effects of glyciram, pantohematogen, granulocytic CSF, and D-glucuronic acid preparation on the granulocytic lineage hemopoiesis suppressed by cyclophosphamide or 5-fluorouracil. The effects hemostimulators against the background of 5-fluorouracil treatment were less pronounced that during cyclophosphamide treatment.

Pronounced regenerative effects of alkaloid napelline extracted from Aconitum baicalense on granulocytic hemopoiesis were revealed in the model of cytostatic myelosuppression. Activation of functions of hemopoietic progenitor cells along with increased feeder capacity of the stromal elements in the hemopoiesis inducing microenvironment with decreased levels mesenchymal progenitor cells in the bone marrow are the mechanisms underlying the hemostimulating action of this substance.

A mixture of diterpene alkaloids of Aconitum baicalense exhibited pronounced regenerative hemostimulating properties on the model of cytostatic myelosuppression. The therapeutic effect is based on activation of hemopoietic progenitor cells against the background of increased feeder capacity of stromal compartment of the hemopoiesis-inducing microenvironment and decreased count of mesenchymal stem cells in the bone marrow.

We compared hemostimulating activity of glycyram and a preparation of D-glucuronic acid on the model of granulocytic hemopoiesis suppressed by 5-fluorouracil. Different mechanisms were shown to underlie activation of hemopoiesis by the above preparations: D-glucuronic acid directly affects hemopoietic cells, while glycyram modulates local mechanisms regulating hemopoiesis.

We studied the effect of mobilization of bone marrow multipotent stem cells induced by intragastric administration of pegylated hyaluronate-endo-β-N-acetylhexosaminidase (Peg-HEAHA) on hemopoiesis under conditions of experimental chronic hepatitis. Peg-HEAHA increased the counts of hemopoietic precursors in the hemopoietic tissue against the background of their decelerated maturation. This was paralleled by a short-term decrease in the count of neutrophilic granulocyte in the bone marrow and a slight increase of neutrophil count in the peripheral blood.

We evaluated whether immobilized hyaluronidase can modify the hematotropic effect of immobilized granulocyte CSF (G-CSF). The preparation of immobilized hyaluronidase (50 arb. units per mouse) potentiated the specific effect of immobilized G-CSF on granulomonocytopoiesis. The preparation was shown to facilitate the indirect effect of immobilized G-CSF on hemopoiesis (stimulation of the erythroid and lymphoid hemopoietic stems). These changes were accompanied by an increase in functional activity of hemopoietic precursor cells, secretion of humoral factors by bone marrow myelokaryocytes, and concentration of hemopoietins in the serum.

We compared hemostimulating activity of pantohematogen and granulocytic CSF under conditions of 5-fluorouracil-induced cytostatic myelosuppression. It was found that activation of hemopoiesis regeneration under the effect of the test preparations was accompanied by the development of hyperplasia of the granulocytic and monocytic hemopoietic bone marrow lineages and more rapid recovery of the count of pholymorphonuclear leukocytes and monocytes in the peripheral blood (more marked under the effect of pantohematogen) followed by neutrophilia and monocytosis.

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 effect of Dicarbamin preparation on hemopoiesis suppressed with cyclophosphamide was studied in animal experiments. It was shown that Dicarbamin produced a protective effect on granulocytic hemopoietic steam. This property of the preparation is determined by both protection of immature granulocytic cells at early terms after cytostatic treatment and more active maturation of neutrophils in the bone marrow due to enhanced secretion of humoral factors by elements of hemopoietic environment at late terms of the experiment.

We studied the effect of immobilized hyaluronidase on hemopoiesis under conditions of cyclophosphamide-induced suppression. The preparation was shown to possess high hemostimulating activity. The stimulatory effect of hyaluronidase on the erithron was more pronounced than its effect on the granulocytic hemopoietic stem due to increase in functional activity of hemopoietic precursors and hemopoiesis-inducing microenvironment.

Preparation containing ultralow doses of antibodies to stem cell factor considerably activates bone marrow myelopoiesis suppressed by cyclophosphamide. This effect of the preparation is based on stimulation of proliferation of committed hemopoietic precursors and increase in functional activity of adherent elements of hemopoiesis-inducing microenvironment.

The hemostimulatory effects of granulocytic CSF, immobilized on polyethyleneglycol using radiation synthesis nanotechnology, were studied on the model of cyclophosphamide-induced myelosuppression. Immobilization of granulocytic CSF led to stimulation of granulomonocytopoiesis by increasing functional activity of granulomonocytic precursors and secretion of humoral factors by elements of hemopoiesis-inducing microenvironment, and due to more intensive formation of hemopoietic islets. The granulocytopoiesis-stimulating effect of immobilized granulocytic CSF was comparable to the effect of standard nonconjugated granulocytic CSF. Specific activity of immobilized granulocytic CSF in oral treatment was demonstrated.

Exhaustion of catecholamine depot in the CNS before modeling of cytostatic myelosuppression potentiates the stimulatory effect of granulocytic CSF on regeneration of the granulocytic hemopoiesis stem. The increase in granulocyte count in the blood system under these conditions is caused by recovery of the structural and functional organization of the hemopoietic tissue (at the expense of reduction of the suppressive effect of catecholamines on the formation of granulocytic hemopoietic islets) and simultaneous stimulation of division and maturation of granulomonocytic precursors.

The possibility of using ultralow-dose cyclophosphamide for reducing the myelotoxicity of cyclophosphamide, injected in the maximum permissible dose, was studied in mice. Combined treatment by the cytostatic and its ultralow-dose preparation led to a lesser suppression of the erythroid, lymphocytic, and particularly granulocytic hemopoiesis stems. This effect is explained by stimulation of the secretory activity of hemopoiesis-inducing microenvironment and hence, of the functional activity of granulocytopoiesis under the effect of ultralow-dose cyclophosphamide.

The content of hemopoietic precursors in the bone marrow, its morphological composition, production of hemopoietic growth factors by cells of the hemopoietic microenvironment, erythropoietic activity, and plasma content of endogenous erythropoietin were studied in CBA/CaLac mice with hypoplasia of hemopoiesis induced by adriamycin in a maximum permissible dose. Cytostatic treatment affected production of substances determining erythropoietic activity by adherent and nonadherent cells of the bone marrow. Erythropoietic activity of peripheral blood plasma considerably increased. Recovery of erythroid hemopoiesis was determined by the effects of endogenous erythropoietin and other substances secreted by cells of the hemopoietic microenvironment and present in the peripheral blood.

The myelotoxicity and the hemopoiesis recovery effect of etoposide, an antitumor preparation of the podophyllotoxin group, were experimentally studied on mice. It was found that the main role in the hemopoiesis recovery after etoposide administration is related to accelerated proliferation and increased differentiation of the hemopoietic precursor cells.

Pantohematogen stimulates hemopoiesis in mice with cyclophosphane induced bone marrow hypoplasia. The hemopoiesis recovery activated by pantohematogen is manifested by the granulocyte lineage hyperplasia in the bone marrow, rapid restoration of the polymorphonuclear leukocyte and monocyte counts in the peripheral blood, and the development of neutrophilia and monocytosis. The activation effect of pantohematogen on the bone marrow hemopoiesis is related to stimulating the precursor cell proliferation and differentiation and to increasing the functional activity of the hemopoietic microenvironment.

Specific biological activity of the domestic preparation of recombinant human erythropoietin (RHEPO) in an original pill form was experimentally studied in vitro and in vivo. Administration of the RHEPO parent substance at a concentration of 0.5 10 U/ml significantly accelerated the growth of erythroid colony-forming cells (CFU-E) in the culture of intact nonadherent myelokaryocytes. The erythropoiesis-stimulating properties of the new RHEPO preparation are comparable with those of the well-known injection preparations. The drug action is related to increasing the erythroid cell content in the bone marrow and the reticulocyte and erythrocyte counts in the peripheral blood.

The hemostimulating activity of the drug glycyrram and the recombinant granulocytic-macrophagic colony-stimulating factor (CSF) was compared on models of myelosuppression induced by injection of an alkylating agent cyclophospane (CF) or the antimetabolite 5-fluorouracil (5-FU). It was found that glycerram stimulated hematopoiesis more effectively after 5-FU injection but to a lesser extent (in relation to CSF) in CF injection.

Whether cytostatic-induced disorders of the blood system can be corrected with D-glucuronic acid has been studied in murine experiments. D-glucuronic acid has been demonstrated to selectively stimulate the processes of bone marrow granulomonocytopoiesis both in intact animals and in rats with bone marrow hypoplasia induced by cyclophosphanum. During D-glucuronic acid administration, stimulation of hemopoietic regenerative processes is followed by the development of granulocyte lineage hyperplasia in bone marrow, the rapid restoration of blood polymorphonuclear leukocyte and monocyte counts and the development of neutrophilia and monocytosis.

The mechanisms of regulating influence of D-glucuronic acid on granulomonocytopoiesis++ have been studied by using the model of cyclophosphamide-induced myelodepression. Increase of colony-stimulating and interleukin-1 activities production by hemopoiesis inducing microenvironment cells, the stimulation of hemopoietic islets and the different granulomonocytopoiesis precursor cells forming have been shown to be the base of activating action of D-glucuronic acid on bone marrow granulomonocytopoiesis recovery.

Acute infectious peritonitis simulated in mice was used to show that previous osmotic deterioration of the abdominal mast cell population significantly influenced the function of hemopoiesis-inducing microenvironment (HIM). The earlier production of the colony-stimulating and erythropoietic activities by the non-adhesive myelokaryocytes and the decreased production of these activities by the adhesive cells have been established. The results obtained evidence that mast cells modulate HIM mediating their influence on hemopoiesis under natural conditions of inflammation.

A model of acute infectious peritonitis in mice demonstrated that the inflammation is attended by marked biphasic activation of bone-marrow granulomonocytopoiesis and that the activation is due in many respects to increased functional activity of elements forming the hemopoiesis-inducing microenvironment. This was suggested by increased colony-stimulating activity of the marrow mononuclear cells and the content of hemopoietic islets in the marrow. The colony-stimulating activity of peripheral blood also increased. It was established that inflammation is also characterized by activation of bone-marrow erythropoiesis, which is linked with increased erythropoietic activity of the hemopoiesis-inducing microenvironment and blood. There was a relation between the hemopoietic changes and the kinetics of leukocytes in the focus of inflammation.

The influence of enkephalins on the medullary hemopoiesis has been studied during stress reaction in noninbred mice. It was shown that leu-enkephalin administration suppressed, while met-enkephalin injection stimulated granulocyto- and erythropoiesis during immobilization stress.

The role of thymus in the regulation of erythropoiesis during stress has been studied in experiments on immobilized mice. The development of pronounced leukopenia due to stimulation of erythro- and granulocytopoiesis was demonstrated. Thymectomy, performed a month before immobilization, abolished the phenomenon of erythropoietic cellularity, indicating an important role of thymus in the regulation of myelopoiesis during stress.