The cholinergic system is involved in regulation of the development of the hematopoietic system

Gene expression profiling demonstrated that components of the cholinergic system, including choline acetyltransferase, acetylcholinesterase and nicotinic acetylcholine receptors (nAChRs), are expressed in embryonic stem cells and differentiating embryoid bodies (EBs). Triggering of nAChRs expressed in EBs by nicotine resulted in activation of MAPK and shifts of spontaneous differentiation toward hemangioblast. In vivo, non-neural nAChRs are detected early during development in fetal sites of hematopoiesis. Similarly, in vivo exposure of the developing embryo to nicotine resulted in higher numbers of hematopoietic progenitors in fetal liver. However postpartum, the number of hematopoietic stem/progenitor cells (HSPC) was decreased, suggesting an impaired colonization of the fetal bone marrow with HSPCs. This correlated with increased number of circulating HSPC and decreased expression of CXCR4 that mediates migration of circulating cells into the bone marrow regulatory niche. In addition, protein microarrays demonstrated that nicotine changed the profile of cytokines produced in the niche. While the levels of IL1alpha, IL1beta, IL2, IL9 and IL10 were not changed, the production of hematopoiesis-supportive cytokines including G-CSF, GM-CSF, IL3, IL6 and IGFBP-3 was decreased. This correlated with the decreased repopulating ability of HSPC in vivo and diminished hematopoietic activity in bone marrow cultures treated with nicotine. Interestingly, nicotine stimulated the production of IL4 and IL5, implying a possible role of the cholinergic system in pathogenesis of allergic diseases. Our data provide evidence that the nicotine-induced imbalance of the cholinergic system during gestation interferes with normal development and provides the basis for negative health outcomes postpartum in active and passive smokers.     

Effect of thymus cells on the radiosensitivity and differentiation trends of hematopoietic stem cells]

A stimulating influence of thymus cells on the capability of irradiated (from 100 to 500 r) bone marrow of mice of producing colonies in spleen of syngenous recipient has been proven. The intensification of colony formation involves an increased radioresistance of stem cells. It is supposed that radioresistant thymus cells have a stimulating effect. Thymus cells exert their influence not only to the rate of survival of stem cells proliferating in the bone marrow of femur, but also increase their erythropoetic potention.     

Intra-systemic inhibitors of the hematopoietic system]

Physiological, experimental and theoretical aspects concerning haemopoietic inhibitors are reviewed. In the paper there are also discussed future research directions of this branch of haematology.     

The role of the lymphoid system in the regulation of the blood glucose level.

Recent findings have led to a new hypothesis in which it is proposed that the immune system plays a role in regulating the increase in blood glucose levels after a meal. The relevant findings are: (1) the primary lymphoid tissue, the lymph nodes are mostly present within adipose tissue depots throughout the body (there are at least 12 such depots and about 10 (12) lymphocytes, 99% of which are present in lymph nodes); (2) lymphocytes and other immune cells utilize glucose at a high rate but almost all of it is converted to lactate which accumulates in the cells prior to release; (3) glutamine, some of which is synthesized in muscle from glucose, is utilized at a high rate by immune cells, the end-product of which is mainly aspartate, which also accumulates in the cells prior to release; and (4) finally, there is a common blood supply to the lymph node and the adipose tissue depot and the blood flow through the depot and hence the node is increased after a meal. It is proposed that, after a meal, some of the absorbed glucose is taken up from the blood by the lymphocytes and converted to lactate and glutamine is converted to aspartate. These are released slowly into the blood from where they are removed and converted to glycogen by the liver. Hence the immune cells provide a temporary buffer for glucose in the form of lactate and aspartate and, in this way, restrict the rise in blood glucose during and after a meal.     

Modeling regulation mechanisms in the immune system

We develop a mathematical framework for modeling regulatory mechanisms in the immune system. The model describes dynamics of key components of the immune network within two compartments: lymph node and tissue. We demonstrate using numerical simulations that our system can eliminate virus-infected cells, which are characterized by a tendency to increase without control (in absence of an immune response), while tolerating normal cells, which are characterized by a tendency to approach a stable equilibrium population. We experiment with different combinations of T cell reactivities that lead to effective systems and conclude that slightly self-reactive T cells can exist within the immune system and are controlled by regulatory cells. We observe that CD8+ T cell dynamics has two phases. In the first phase, CD8+ cells remain sequestered within the lymph node during a period of proliferation. In the second phase, the CD8+ population emigrates to the tissue and destroys its target population. We also conclude that a self-tolerant system must have a mechanism of central tolerance to ensure that self-reactive T cells are not too self-reactive. Furthermore, the effectiveness of a system depends on a balance between the reactivities of the effector and regulatory T cell populations, where the effectors are slightly more reactive than the regulatory cells.     

Pharmacological regulation of opioidergic antinociceptive mechanisms]

Naloxone-depending potentiation of morphine antinociception by some non-opioidergic compounds between different classes of drugs was found in experiments on mice using nociceptive stimuli of different modality. This potentiation can or cannot be bound with elevation of sensitivity of opioid receptors, release of endogenous opioids or destruction of blood-brain barrier function mor morphine peripheral administration. This potentiation named as "release of functional reserve of opioid antinociceptive response" can or cannot be accompanied by an increase of breathing function depression. Taking into account the data of literature about the dissociation of analgetic positive-supporting morphine effects and also the capability of some compounds to lower the narcogenic opiates potential, the supposition about the real possibility of creating combined drugs is made.     

Somatic pairing of centromeres and short arms of chromosome 15 in the hematopoietic and lymphoid system

Normal human bone marrow and peripheral blood leukocytes as well as malignant cells from a variety of leukemias and lymphomas, demonstrate somatic pairing of centromeres and p arms of chromosome 15 during interphase. This phenomenon, effected by sequences on the p arm and requiring the intranuclear transport of spatial domains for at least one of the homologs, was not seen in amniotic fluid cells, uterine cervical tissue or in tissue fibroblasts. These studies contribute to the recent evidence of somatic pairing of homologous chromosomes in man and provide support for mobile chromosomal domains in interphase. It appears that sequences on the p arm of chromosome 15, possibly the nucleolar organizing genes, are uniquely important in the maturation of benign and malignant cells of hemato-lymphopoietic origin.     

Influence of thymectomy on the lymphoid regeneration of hematopoietic bone marrow after sublethal irradiation]

In C57BL mice, bone marrow lymphoid regeneration after a sublethal irradiation is modified by a graft of normal marrow cells. This effect is suppressed in thymectomized mice since a lymphoid peak is observed after a 350 R irradiation; its composition is heterogeneous: small lymphocytes, lymphoblasts and peculier cells named "X cells". The same phenomenon is observed in mice where all the thymocytes and thymus derived and peripheral lymphocytes are destroyed. These results exclude that bone marrow lymphoid regeneration after irradiation is due to a migration of lymphoid cells of thymic origin to the marrow. They could be explained by the effect of a humoral thymic factor on marrow lymphopoiesis.     

Effect of age of mouse recipients on the functional activity of transplanted hematopoietic and lymphoid cells]

When transplanting the bone marrow cells from adult C57BL mice to the lethally irradiated (CBA X C57BL) F1 hybrids of different age, the decrease of the colony forming activity of the stem haemopoietic cells was observed in the spleen of the older recipients, as compared with the 3 months old ones. The joint transplantation of the bone marrow and thymus cells resulted in both the cases in the stimulation of the growth of colonies. The number of endogenous colonies of haemopoietic cells arising in the spleen of animals following the sublethal irradiation was greater in younger hybrids. After the induction of the "transplant versus host" reaction by the lymph node or spleen cells from the CBA mice, the relative weight of spleen and regional lymph node, respectively, in the older recipients exceeded those in the younger ones.     

Effect of sera against aggregated mouse immunoglobulins on a population of lymphoid and hematopoietic cells]

The in vitro treatment of the mouse spleen cells immunized by the ram erythrocytes with the rabbit and mouse sera against the thermoaggregated mouse immunoglobulins resulted in the inhibition of antigen binding receptors of rosette forming cells. The mouse serum, unlike the rabbit one, induced the inactivation of receptors in rosette forming lymphocytes both in the non-immune and immune mice on the 8th day after the antigenic stimulation. The treatment of bone marrow cells from the intact mice with these sera increased insignificantly the number of hemopoietic colonies in the spleens of lethally irradiated syngenic recipients and stimulated markedly the migration of spleen cells. This may be due both to the direct effect of these sera and to their mediated (through the humoral factor) influence. The inactivation of antigen binding receptors in the spleen rosette forming cells suggests the presence of immunoglobulins on the membrane of B-lymphocytes in the aggregated state or in the form of antigen--antibody complexes.     

Effect of fibroblasts from monolayer cultures of hematopoietic and lymphoid tissue on the immune response in vitro]

Stromal fibroblasts from the monolayer cultures of human bone marrow, guinea pig bone marrow, spleen, thymus and peripheral blood suppressed the response of the plagueforming cells against sheep erythrocytes in the suspension cultures of mouse spleen cells. Combined cultivation of 20 X 10(6) fibroblasts from all the mentioned sources led to complete suppression of the immune response. This suppression was less in mice immunized three days before the spleen cell explantation into the suspension cultures and was absent entirely in case the pre-immunization of spleen cell donors was accomplished nine days before the explantation.     

Neoplastic diseases of the hematopoietic system and ischemia of the lower limbs]

The possible interaction between hematopoietic neoplasms and ischemia of the lower limbs in patients with both pathologies was subjected to analysis. Anaemia, polycythemia, thrombocythemia, increased leucocytosis in the peripheral blood, and hyperuricemia exerted unfavourable effect on the blood flow through the arteries of the lower limbs. In some cases effective cytostatic treatment diminished the ischemia of the lower limbs. Interactions between various drugs used in the chronic treatment of both pathologies in the same patient was also examined.     

Central nervous system mechanisms of arterial pressure regulation

This paper provides a review of recent developments in the field of neural and humoral control of the cardiovascular system mediated through the central nervous system. The areas covered include central mechanism of baroreceptor reflex control, sites of origin of tonic vasomotor activity, interactions between forebrain and brain stem, central actions of humoral factors, the role of visceral and somatic afferents, and the potential for central selectivity of vasomotor control.     

Molecular mechanisms of regulation of the contractile apparatus of smooth muscles]

This review describes the main ultrastructural features, molecular organization and regulation of smooth muscle contractile machinery. Possible molecular mechanisms of smooth muscle sensitization to Ca2+, Ca(2+)-independent contraction and latch state are discussed.