The dose dependence of the development of compensatory-restorative body reactions to irradiation. The EPR method]

The study deals with the mechanism of organism's adaptive responses to the effect of radiation in widely ranging dose. Post-irradiation metabolic changes were evaluated in canine blood as well as in murine blood, spleen, bone marrow and liver using the EPR spectroscopy. It was shown that the dynamics of changes in transferrin and ceruloplasmin pools and ribonucleotide reductase activity were phase-dependent with the maxima at the 2nd, 6th and 10-12th days after irradiation. Such dynamics was observed at various irradiation doses applied. The data allow us to suggest that the nonspecific compensatory--adaptive reactions of organisms develop as the response to irradiation. The dose-response function of the reaction intensity was found to be linear. The shape of the dose-response curve indicates that the minimum response of organism depends on the dose linearly up to 3.2 Gy (for dogs) as well as the maximum one. However, in the case of low-dose irradiation (0.25 or 0.5 Gy) there were deviations of maximum responses from the linearity, i.e. the amplification of the amplitude of compensatory adaptive reactions. These effect were shown to be dependent upon initial individual characteristics of animal blood and to be related to the "depressed" or "activated" state of organism prior to irradiation. The ribonucleotide reductase activity was measured in bone marrow and spleen of animals by the EPR method. The nature of non-repairable DNA damage is discussed in view of the inactivation of ribonucleotide reductase.     

Radioprotective activity and toxicity of copolymer 2-methyl-5-vinyl pyridine with 2-methyl-5-vinylpyridinium-n-oxide

In experiments in mice, hamsters and dogs therapeutic radioprotective efficiency and toxicity of new water-soluble copolymer were studied. It was found that at intramuscular injection of the copolymer to dogs in a dose of 5 mg/kg 24 h after irradiation with a dose of 3.30 Gy (LD85/45) it showed pronounced therapeutic effect (68.1%). In mice and hamsters, the effect was less pronounced: 42-21% after irradiation with a dose of 8.0 Gy. The copolymer is low toxic substance and according to the State standards of Russian Federation belongs to the fourth class (harmless).     

Characteristics of the development of interphase death of hematopoietic tissue in dogs in response to gamma irradiation

In experiments with 2-3 week dogs it was shown that whole-body gamma-irradiation with a dose of 3 Gy causes an insignificant absolute rise in the amount of degrading chromatin of the haemopoietic organs during the first 24 h following irradiation. After 48 h, this cell death parameter is normalized. A considerably lower radiosensitivity of lymphoid cells of dogs compared to small laboratory animals is indicated by a stable DNA content per 1 g of thymus, intactness of its structure after irradiation, and the absence of an increase in thymidine content of blood of young and adult dogs under the effect of 3-3.7 Gy radiation.     

Two variants of loss of sight (blindness) after local irradiation of the head in cats and dogs

After local irradiation of heads with doses of 50 to 100 Gy cats and dogs exhibited two types of a loss of sight: early blindness (during the first two hours) noted only in cats after a dose of 100 Gy, and delayed blindness in cats after a dose of 50 Gy, and in dogs after all doses under study.     

Effect of continuous, whole-body gamma irradiation upon canine lymphohematopoietic (CFU-GM, CFU-L) progenitors and a possible hematopoietic regulatory population

Clonogenic assays for granulocytes-macrophages (CFU-GM) in bone marrow and for T lymphocytes (CFU-L) in peripheral blood were performed on dogs continuously exposed to 60Co irradiation (0.02, 0.04, or 0.11 Gy/day). When decreased numbers of CFU-GM were observed they correlated well with the clinical status of the dogs but were not generally associated with increasing cumulative doses of absorbed irradiation. In clinically normal, irradiated animals, decreased CFU-GM values and myeloid-erythroid ratios were observed, suggesting that chronic irradiation may affect the granulocytic series well before decreased peripheral blood values are seen. In hypocellular dogs the number of CFU-GM were significantly decreased compared to values obtained from control or clinically normal irradiated dogs, while virtually no CFU-GM were observed in the leukemic dogs. Only the CFU-GM values of the hypocellular group showed an association, e.g., a suggestion of an abortive regenerative effort, with increasing absorbed dose. Proliferative capacity of T lymphocytes (CFU-L) was not affected by either increasing absorbed irradiation or the presence of leukemia. D0 values were determined on marrow fibroblastic cells to ascertain whether a radioresistant subpopulation of stromal elements would result from continuous in vivo irradiation. No correlation was found between absorbed dose and increased D0 values. However, seven of eight dogs which developed acute nonlymphocytic leukemia displayed marrow fibroblastic cells with elevated D0 values. These radioresistant marrow fibroblastic cells were assayed for their ability to support normal granulopoiesis and found to be not significantly different from control fibroblasts.     

The dynamic content of prostaglandins and cyclic nucleotides in the blood of irradiated dogs and monkeys

In experiments with dogs and monkeys a study was made of the dynamics of the content of prostaglandins (PG) and cyclic nucleotides after gamma irradiation. In dogs irradiation with lethal doses (3.1 and 50 Gy) caused a short-term, evidently stress growth of cAMP, PGE and PGF2 alpha levels. At the height of radiation sickness PGF2 alpha and cGMP content decreased considerably. Irradiation of monkeys with a nonlethal dose of 3.2 Gy changed PGE and PGF2 alpha levels to a lesser extent, while concentrations of cyclic nucleotides varied but their ratio remained stable.     

Localisation of the Site of Action of tube growth stimulation by micro UV-irradiation of pine pollen

Summary Micro-irradiation of pine pollen grains was carried out with different doses at four different dose rates and the tube growth was observed. The irradiation of the whole pollen grains in the dehydrated state and dorsal position and of those in the hydrated state and ventral position induced stimulated tube growth after receiving low doses of UV light. The effect of stimulation depended on the ratio between dose and dose rate. After partial irradiation of pollen grains at low doses, carried out with the technique of blind shot, a stimulation effect could also be observed. It was calculated that the irradiation of the cytoplasm had a strong, the irradiation of the active nucleus (vegetative) had a moderate and the irradiation of the dormant nucleus (generative) had little or no dose rate dependance. The dose effect of the nuclei showed a reverse tendency to the dose effect of the cytoplasm. Experiments with different light filters suggested that the dose rate dependance of the cytoplasm is probably not caused by a repair mechanism. The vegetative nucleus showed an effect of photoreactivation and probably also of a dark repair. The generative nucleus exhibited only an effect of photoreactivation.Dedicated to Prof. Dr. Ing. H. Glubrecht on the occasion of his 60. birthday     

The effect of recombinant human interleukin-1 beta on the repopulation of bone-marrow colony-forming cells in mice subjected to the action of radiation and burns]

The radioprotective and restorative (therapeutic) effects of human recombinant interleukin-1 beta (IL-1 beta) on the population of bone marrow CFU-S of mice, subjected to either sublethal doses of ionising irradiation itself or the same irradiation in combination with thermal burn, are investigated. Both the effects of the agent are registered under both in vitro and in vivo irradiation in semi-, syn- and allogeneic animals. If the irradiation was combined with thermal burn, the "therapeutic" effect of the agent was demonstrated at irradiation dose equal to 3.06 Gy rather than to 6.12 Gy. If the bone marrow cells were irradiated in vitro in dose 3.06 Gy with the following heat shock at 42 degrees C for 10-20 min, the "therapeutic" effect of IL-1 beta was seen only if it was added to cells before rather than after irradiation. The radioprotective effect of IL-1 beta is maintained under in vitro, as well as in vivo conditions in the allogeneic system of transplantation of the CBA donor bone marrow to the C57BL mice.     

Early cell repair of the lung and the intestine in mice, after irradiation by fast neutrons and gamma rays

Lung tolerance is assessed from LD50 at 180 days after thoracic irradiation, in mice, with d(50) + Be neutrons and 60Co gamma rays. Early intestinal tolerance is assessed from LD50 at 7 days after abdominal irradiation. Additional dose (Dr) to reach LD50 when a single dose Ds is split into 2 equal fractions Di separated by different time intervals "i", is determined (Dr = 2Di - Ds), Dr is larger after gamma than after neutron irradiation, for lung and intestine. After thoracic irradiation with gamma rays, Dr reaches 3.36, 4.38, 5.12 and 5.37 Gy for "i" = 2, 6, 12 and 24 hours respectively; after neutron irradiation, Dr reaches 0.66, 0.9, 1.29, 1.95 and 1.50 Gy for "i" = 1, 2, 4, 12 and 24 hours. Dr is smaller for intestine; after abdominal irradiation with gamma rays, it reaches 1.99, 2.59, 2.74, 3.11, 3.34, 4.44 and 4.56 Gy for "i" = 1, 2, 3.5, 8, 12, 18 and 24 hours; after neutron irradiation, it reaches 0.13, 0.45, 0.42 and 1.33 Gy for "i" = 1.5, 3.5, 5.5 and 24 hours. After gamma irradiation, early repair is complete after 3.5 hours for intestine and needs 12 hours for lung.     

The "shielding" effect of the guide wire during coronary brachytherapy with P-32 source

Intracoronary beta irradiation (use of beta radiation for intracoronary irradiation) is an effective method in reducing neointimal proliferation after successful angioplasty and stent implantation. However, long-term results may be influenced by absolute dose and by the homogeneity in dose distribution. In our study, we investigated dose perturbation due to the presence of a conventional guide wire during irradiation. The Galileo III centering catheter and P-32 beta source were used. The 55 MD GAF Chromic foil was positioned within a phantom made of PMMA. The dose distribution at cylindrical surfaces has been assessed using GAF Chromic dosimetric foil MD55 (Nuclear Associates, USA). Our study demonstrated the significant dose reduction of 46% in the most "shaded" area. The dose reduction to 80% or less occupy the 60 degrees sector. This phenomenon can cause progression of late restenosis. In conclusion, the results suggest that technical improvements in centering catheter construction should be made to eliminate the "shielding" effect of the guide wire.     

Changes in the leukocyte phagocytic activity of donor blood after its UV irradiation. I. Its relation to the irradiation dose and initial level of phagocytic activity

Phagocytic activity of human mono- and granulocytes increased markedly after UV blood irradiation in the apparatus "Izolda" used in hospitals of the USSR for medical treatment. With the rise of irradiation dose the ratio of cells ingesting latex particles increased, although the average number of particles ingested per cell decreased. The integrative phagocytic index poorly depended on the irradiation dose. In patients with a low initial level of phagocytic index, after UV blood irradiation it became more pronounced than in those with the initial elevated level. The enhancement of phagocytic activity is the result of a direct UV-stimulation of cells. This stimulation not mediated by irradiated blood plasma is known to inhibit the phagocytic activity of leucocytes. A possible mechanism of phagocytic activity stimulation is discussed.     

Comparative assessment of the danger of inhaling 239Pu and 241Am based on the degree of leukopenia in dogs

From the analysis of the results of examination of 96 dogs it is concluded that the estimate of a relative danger of breathing transuranium radionuclides with different metabolism rates (polymeric 239Pu and monomeric 241Am), according to degree of leukopenia is more reliable when it is compared with a mean weighed dose per whole organism than the dose per individual "critical" organ.     

A multifactorial study on the relative postradiation changes in various categories of behavioral reactions in rats

The use of the methods of multifactor, orthogonal and composition planning in studying the behavioural disturbances in rats after gamma irradiation with doses of 0.258 to 1.29 C/kg and the application of the proposed method of discrimination of effects by empirical models permitted to establish the informative and adequate dependences of the probability of these disturbances on dose of nonuniform irradiation and the degree of strengthening of the conditioned reflex. It was shown that the effect of radiation decreased, in a discrete manner, the probability of making the first decision by rats in a behavioural task (here we deal with the "dose-response" function). The average time of making the first decision after irradiation was invariable within the dose range under study. Within the range of the studied factors both the value of the dose of whole-body irradiation and the degree of strengthening of the conditioned reflex significantly affected the probability of fulfilling the task by the animals the significance of the radiation dose being several times higher. The effects of the interaction of the two factors, that is, irradiation and the degree of the radiation affection, were insignificant in changing the behavioural reactions under study.     

Influence of radiation dose patterns on lung tumor incidence in dogs that inhaled beta emitters: a preliminary report

Different radiation dose patterns to the lung from inhaled beta-emitting radionuclides may influence the frequency and kind of biological effects. To determine the magnitude of this influence, groups of Beagle dogs were exposed to aerosols of 90Y, 91Y, 144Ce, or 90Sr in relatively insoluble particles and observed for their life spans. Different dose patterns were achieved by using these radionuclides having similar beta emissions and chemical form but having physical half-lives ranging from 2.6 days to 28 years. The range of initial lung burdens of radionuclides studied resulted in a range of biological effects from early deaths at the highest radiation doses to no discernible effects at the lowest doses. The effective half-lives of the four radionuclides in the lung ranged from 2.5 to 600 days. Within 1.5 years after exposure, some dogs died with radiation pneumonitis and pulmonary fibrosis. Between 1.5 and 10 years after exposure, 42 pulmonary carcinomas and 28 pulmonary sarcomas were observed in 163 dogs that died. Protracted irradiation of the lung from 90Sr or 144Ce resulted in a relatively high radiation dose and produced more total lung tumors but fewer lung tumors per rad than less protracted irradiation from 90Y or 91Y. At 10 years after inhalation exposure, the difference in risk per rad among the different dose patterns was a factor of 4 to 8, indicating that the different radiation dose patterns from inhaled beta emitters do influence lung tumor risk factors, at least at high (greater than 20,000 rad) doses to lung.     

The antiradiation properties of the ecdysteroid-containing compounds

The antiradiation properties of the ecdysteroid-containing preparations ("serpisten" and inokosterone) are studied under their application before or after the 22.6 cGy chronic low intensity gamma-irradiation of mice. It is shown that the antiradiation of these compounds depend on the dose of preparations and time of the application before or after irradiation of mice. "Serpisten" prevented the decrease of the growth of the body mass of irradiated mice. The normalization of the phospholipid composition of the mice liver and blood erythrocytes for the most investigated parameters revealed under the application of this compound at the dose of 50 mg/kg after the irradiation of animals. The capacity of "serpisten" to decompose of peroxides is shown in vitro. Inokosterone had the certain anabolic properties, caused the normalization of the total peroxidase activity of blood and intensity of the lipid peroxidation (LPO) in brain and in liver, and also the repair of the interrelation between the LPO intensity and catalase activity in the irradiated mice liver. The obtained results allow to conclude that the antiradiation properties of the ecdysteroid-containing preparations under the chronic low intensity irradiation of animals at the low dose due to their capacity to depend on the LPO regulatory system parameters.     

Quantitative regularities of development of endogenous infection in irradiated organism (survey of literature)

Statistical analysis of data from the literature and the author's own experimental results was carried out in order to reveal functional dependence between the dose of irradiation and the development of endogenous infection in an irradiated organism. Direct linear dependence was established between the dose of irradiation and the severity of endogenous infection at doses causing death from the "bone-marrow" syndrome in acute radiation sickness. In the case of death from the "intestinal" syndrome, inverse linear dependence can be observed between the dose of irradiation and the culture yield of microbes from internal organs. In this case, the pathological effect on the organism is due to bacterial endotoxins formed during disintegration of microbial cells in the organism. Endogenous infection and endotoxinaemia essentially aggravate the course of acute radiation disease. The importance of endogenous infection in death of the organism is neutralized after irradiation in doses causing death "under the ray".     

Effect of external gamma radiation on shortening the life expectancy and rates of the formation of absorbed doses from incorporated 239Pu in dogs

External gamma irradiation of dogs with doses of 103.2 and 51.6 mC/kg combined with the effect of inhaled plutonium-239 accelerates the formation of absorbed doses in secondary organs of the radionuclide deposition by 41.7 and 2.4 times, respectively, whereas the dose of 25.8 mC/kg is ineffective. As estimated by the rate of 239Pu accumulation and by the life span shortening, the minimum effective and the maximum ineffective doses are 104.8 and 80.5 cGy and 89.2 and 79.2 cGy, respectively.     

Early radiation response of the canine heart and lung

In this study three groups of four adult beagle dogs were irradiated with a 12-Gy single dose to the thorax. The fields used were the entire thorax, the entire thorax with a heart block in place, and the heart with one-third of the lung volume. The response of the lung was evaluated by cellular and biochemical analysis of sequential bronchoalveolar lavage fluids, blood gas analysis, physical examination, and histopathology. Sparing a small volume of lung improved survival. Cardiac function was evaluated by right heart catheterization, echocardiography, physical exam, and histopathology. Pulmonary artery pressure was increased in all dogs, mean systemic artery pressure was decreased in all dogs, and no difference could be shown among the groups. These effects are likely secondary to a reduced pulmonary capillary volume. Stroke volume was significantly deceased in dogs that had their hearts included in the field but not in dogs with their hearts shielded. This effect was not thought to be secondary to lung injury. The influence of lung irradiation on cardiac function was limited to pulmonary hypertension. Pulmonary hypertension may be enhanced by the release of vasoactive compounds. Pulmonary hypertension may contribute to radiation-induced heart failure.     

Effect of autologous marrow transplantation on bone marrow recovery following large-field fractionated irradiation of dogs

After large-field fractionated irradiation of dogs at a cumulative dose of 54 Gy, a stable bone marrow depletion occurs persisting for a year following irradiation. The automyelotransplantation after the end of the exposure elicits a transient recovery of the exposed bone marrow, 1.5-2 months after the beginning of irradiation, followed by a secondary depletion of the exposed haemopoietic sites. The control and the automyelotransplanted animals exhibited bone marrow recovery one year and six months after irradiation, respectively, the cellularity being maintained at a high level for 3 years of observation.     

Time- and dose-dependent post-irradiation changes of Fe3+-transferrin and Cu2+-ceruloplasmin pools in blood, their influence on ribonucleotide reductase activity in animal tissues and the effects of radioprotectors

The time- and dose-dependent changes of Fe(3+)-transferrin (Fe(3+)-TF) and Cu(2+)-ceruloplasmin (Cu(2+)-CP) pools, of superoxide dismutase activity and the inhibitory activity of alpha 2-macroglobulin in blood as well as changes in synthesis rates of deoxyribonucleotides (dNTP), DNA and proteins in organs (spleen, liver, bone marrow, thymus) of mice and dogs given total body irradiation have been studied using of ESR spectroscopy, radioisotope techniques and biochemical determination of enzymatic activity. The experimental data have allowed us to reveal the sequence of organism's response reactions against irradiation and their modifications by radioprotectors. Changes in blood Fe(3+)-TF pool is one of the most informative, highly radiosensitive and rapidly reactive marker against irradiation and drug administrations. This irontransport protein controls a rate-limiting iron-dependent stage for DNA synthesis--the synthesis of dNTP, catalyzed by iron-containing ribonucleotide reductase (Fe(3+)-RR). It has been shown that time-dependent post-irradiation changes of Fe(3+)-TP pool in blood are characterized by three distinct stages: 1) the prompt increase of pool (SOS-type response) playing the important role in protecting of cell's genetic apparatus from damage; 2) the decrease of its pool within 3-18 h after irradiation resulting in the loss of Fe(3+)-RR activity in tissues of blood-forming organs that make more stronger radiation-induced damage; 3) the following phase-dependent increase in Fe(3+)-TF pool at the 2-nd, 6th, 10-17th days after irradiation due to an increase in transferrin synthesis. This increase may be considered as compensatory reaction of blood-forming organs directed at restoring blood and organ's cells. The time-dependent courses of the reactions are independent from radiation doses indicating to the universal and nonspecific response of organism against irradiation. But, the intensity of this compensatory-adaptive response at 2-nd and 6th days grows with increasing radiation dose up to lethal that, and organism's response becomes abnormal and physiologically hypertrophic. The prolonged "stressful syndrome of biochemical tense state" should be attributed to negative effects for organism, since it may result in the failure of compensatory adaptive organism's reactions and animal killing. The radioprotectors ward off the appearance of this dangerous state. Dogs with initial individual characteristics of blood which were typical for "suppressed" or "activated" states had abnormal response against irradiation by low doses 0.25 or 0.5 Gy. In these cases the intensity of response reactions of organism was essentially increased and markedly deviated from linear dose dependence. The phase-dependent increase of Fe(3+)-TF pool in blood in post-irradiation time resulted to the increase of Fe(3+)-RR activity in blood-forming organs. The key event ensuring the development of compensatory adaptive reactions is the increase of capacity of protein-synthesizing apparatus, the activation of biosynthesis of dNTP and DNA against the treatment with damaging factors.