40th COSPAR Scientic Assembly 2014

Life Sciences as Related to Space (F) Molecular, Cellular and Synthetic Biology Research in Space and Ground-based Analogues (F5.5)

HEMATOPOIETIC ACUTE RADIATION SYNDROME (BONE MARROW SYNDROME, APLASTIC ANEMIA): MOLECULAR MECHANISMS OF RADIATION TOXICITY.

Dmitri Popov, dlpopov@rogers.com Advanced Medical Technologies and Systems, Richmond Hill, Canada Slava Maliev, intervaccine@gmail.com Russian Academy of Science, Vladicaucas, Russia Jerey Jones, jajones@bcm.edu Baylor College of Medicine, Houston, United States

Objective: Aplastic Anemia is a disorders of the pluripotential stem cells involve a decrease in the number of cells of myeloid, erythroid and megakaryotic lineage [Segel et al. 2000 ]. Etiology of Aplastic Anemia include idiopathic cases and secondary aplastic anemia after exposure to drugs, toxins, chemicals, viral infections, lympho-prolipherative diseases, radiation, genetic causes, myelodisplastic syndromes and hypoplastic anemias, thymomas, lymphomas. [Brodsky et al. 2005.,Modan et al. 1975., Szklo et al. 1975]. Hematopoietic Acute Radiation Syndrome (or Bone marrow syndrome, or Radiation Acquired Aplastic Anemia ) the acute toxic syndrome usually occurs with a dose of irradiation between 0.7 and 10 Gy (70 1000 rads). [ Waselenko et al., 2004]. The etiology of bone morrow damage from high-level radiation exposure results depends on the radiosensitivity of certain bone marrow cell lines. [Waselenko et al. 2004] Aplastic anemia after radiation exposure is a clinical syndrome that results from a marked disorder of marrow blood cell production. [Waselenko et al. 2004] Radiation hematotoxicity is mediated via genotoxic and specic toxic mechanisms, leading to aplasia, cell apoptosis or necrosis, initiation via genetic mechanisms of clonal disorders such as Aplastic Anemia. Acute Radiation Acquired Aplastic Anemia results from radiation injury to pluripotential and multipotential stem cells in the bone marrow. The clinical signs displayed in reticulocytopenia, anemia, granulocytopenia, monocytopenia, and thrombocytopenia. The number of marrow CD34+ cells (multipotential hematopoietic progenitors) and their derivative colony-forming unitgranulocyte-macrophage (CFU-GM) and burstforming uniterythroid (BFUE) are reduced markedly in patients with aplastic anemia. [ Guinan 2011, Brodski et al. 2005, Beutler et al.,2000] Cells expressing CD34 (CD34+ cell) are normally found in the umbilical cord and bone marrow as hematopoietic cells, a subset of mesenchymal stem cells, endothelial progenitor cells, endothelial cells of blood vessels, etc. [Beutler et al. 2000 ] Potential mechanisms responsible for radiation acquired marrow cell failure include direct toxicity , direct damage of hematopoietic multipotential cells or cel-

lular or humoral immune suppression of the marrow multipotential cells. [ Beutler et al. 2000] Methods: These studies were conducted at several dierent research institutions and laboratories listed as follows: Kazan All-Union Scientic Research Veterinary, Biotechnology Centre of Russian Academy of Science (North Osetia), Institute Belarussian Scientic and Research Institute for Radiobiology in Gomel, the St. Petersburg Veterinary Institute, the Advanced Medical Technology and Systems Inc., Ontario, Canada. The studies were approved by the Animal Care and Use Committee for ethical animal research equivalent, at each institution. A critically important volume of puried Radiation Toxins (RT) was isolated from larger mammalian irradiated animals. Subsequently the RT were characterized chemically and biologically. The experimental design of later studies compared relative toxicity, potential for development of acute radiation hematopoietic syndrome, and potential cloning disorder of multipotential hematopoietic progenitors and their derivative and lethality after intravenous or intramuscular injections of SRD containing Hematopoietic Radiation Toxins. These experiments have employed a wide variety of experimental and agricultural animals. The animals were irradiated in RUM-17, Puma, and Panorama devices. The dose rate varied from 0.7Gy to 100Gy. The methods of immune depletion, ane immuno-lympho-plasmasorption, as well as direct extraction were used to rene and purify the specic Radiation Toxins from the central lymph of animals with Haemotopoietic forms of Radiation Toxins. Experiments include administration of Haemotopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg. Results: After I/V or I/M administration of Hematotoxoic Radiation Toxins to radiation na ve animals induce developing specic, for aplastic anemia, clinical signs - thrombocytopenia, lymphocytosis continued to lymphocytopenia, granulocytopenia , ecchymosis, hemorrhage and coagulopathy. This important clinical signs of the mimicked hematopoietic acute radiation syndrome. Conclusions: Administration of Haemotopoietic Radiation Toxins (SRD-4) to radiation naive animals in doses 0.1 mg/kg; 0,5 mg/kg; 1 mg/kg; 2 mg/kg; 3 mg/kg up to 30 mg/kg produced specic toxic reactions with development symptoms of the hematological form of Acute Radiation Syndromes. Administration of high doses of Hematopoietic Radiation Toxins developed Severe Acute Radiation Exposure Syndromes and will induce Toxic Multiple Organ Failure (TMOF) and Toxic Multiple Organ Involvement (TMOI) e.g. pneumonitis, renal failure, renal hypo-perfusion, acute tubular necrosis, hepatic failure, etc. as an acute consequences of radiation toxemia. Aplastic Anemia important clinical and pathological process developed after high doses of radiation and radiation toxins.