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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 role of signaling molecules in synthesis of humoral regulators of granulocytopoiesis by the hematopoietic microenvironmental cells during stress was analyzed using specific inhibitors. The major role in stimulation of the synthesis of granulocytic CSF during stressful stimulation is played by PI3K/Akt signaling cascade. Nuclear transcription factor NF-κB plays an auxiliary role in the regulation of functional activity of the bone marrow mononuclears. However, this factor affects the synthesis of granulocytic CSF by CD4 + cells of the bone marrow in response to stressful stimulation. Different degree and specific character of involvement of the signaling proteins in the regulation of the production of humoral factors determining colony-stimulating activity are explained by changes in functional state of monocyte-derived macrophages in different periods of stress response.

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.

The effects of nanotechnology (electron-beam) -PEGylated (or immobilized; Im) hyaluronidase (HD) on the state of the pool of bone marrow progenitor cells and their mobilization induced by granulocyte colony stimulating factor (G-CSF) were studied. A high specific activity of the drug Im-HD on progenitor cells of different classes was demonstrated using parenteral and enteral administration. An increase in the content of erythroid (E), granulomonocytic (GM), fibroblast (F) colony-forming units (CFU) and mesenchymal stem cells (MSC) in bone marrow was shown, as well as G-CSF-induced stimulation of mobilization of precursors into the peripheral blood under the influence of Im-HD. The detected activity of this novel drug on progenitor cells indicates the potential for a safe and highly effective treatment for hematology practice and regenerative medicine.

High hepatoprotective activity of granulocytic CSF and hyaluronidase immobilized using electron-beam immobilization technology was demonstrated on the model of CCl(4)-induced hepatitis: the preparations produced anticholestatic, anti-inflammatory, and antisclerotic effects. These effects developed against the background of stimulation of bone marrow multipotent precursor cells and their mobilization into circulation accompanied by an increase in the content of parenchymatous progenitor cells in the liver. The most pronounced positive effect was observed in combined treatment with the test preparations.

Granulocytic CSF pegylated using electron-beam synthesis nanotechnology exhibits pronounced granulomonocytopoiesis-stimulating and SC-mobilizing activity. More potent stimulation of committed precursors against the background of less pronounced activation of polypotent hemopoietic cells is a peculiarity of hemostimulating action of pegylated using electron-beam synthesis nanotechnology granulocytic CSF in comparison with its non-modified analog. The mobilizing effect of pegylated using electron-beam synthesis nanotechnology granulocytic CSF on early progenitor elements surpasses that of non-conjugated cytokine.

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.

The effect of immobilized granulocyte CSF on morphological characteristics and functional state of the liver was studied during chronic toxic hepatitis. The mechanisms of the therapeutic action of this agent were evaluated. The product had a strong hepatoprotective effect and exhibited the antiinflammatory and antisclerotic properties. The mechanism of activation of reserve systems for cell renewal (involved in restoration of the liver tissue) is probably related to an increase in proliferative activity of early precursor cells in the bone marrow, mobilization of these cells into the peripheral circulation, and directed homing into the liver tissue where they activate local regenerative mechanisms and prevent hepatocyte destruction. It should be emphasized that the concentration of SDF-1 increases in the liver tissue, but decreases in the bone marrow. These changes create the concentration gradient, which determines the migration of undifferentiated precursor cells to the liver.

The mechanisms of hemopoiesis recovery after transplantation of peripheral blood mononuclears obtained using granulocytic CSF and granulocytic CSF in combination with hyaluronidase were studied on the model of cytostatic myelosuppression. It was found that regeneration of the hemopoietic tissue resulted from an increase in the pool of erythroid and granulomonocytic precursors and in their functional activity. The increase in the count of fibroblast precursors in the bone marrow, higher production of hemopoietins by adherent myelokaryocytes, and an increase in the level of humoral factors in the serum were detected after injection of the transplants. A higher therapeutic efficiency of cell material obtained after combined use of granulocytic CSF and hyaluronidase was shown.

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.

We studied processes of proliferation and differentiation of hemopoietic precursor cells in mice treated with granulocyte CSF under conditions of cytostatic myelodepression. It was found that the hemostimulating effect of original granulocyte CSF preparation consists in accelerated maturation of hemopoietic precursors and increased content of DNA-synthesizing CFU-GM in the bone marrow.

We compared hemopoiesis-stimulating activities of dry pantohematogen and recombinant granulocyte colony-stimulating factor under conditions of cyclophosphamide-induced myelosuppression. These preparations stimulated regeneration of bone marrow granulomonocytopoiesis by various mechanisms.