Effects Of Whole-body Irradiation Research Articles

Mitigating effects of hUCB-MSCs on the hematopoietic syndrome resulting from total body irradiation

This study evaluated the clinical and pathologic effects of human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSCs) in the recovery from total body irradiation by comparing it with the effects of granulocyte-colony stimulating factor (G-CSF), an efficacious drug in the treatment of acute bone marrow radiation syndrome. BALB/c mice were treated with G-CSF or hUCB-MSCs after they were irradiated with 7 Gy cobalt-60 γ-rays. Circulating blood counts, histopathologic changes in the bone marrow, and plasma level of Flt-3L and transforming growth factor (TGF-β1) were monitored in the postirradiation period. Hematologic analysis revealed that the peripheral leukocyte counts were markedly increased in the hUCB-MSCs-treated group, whereas G-CSF-treated mice did not recover significantly. Moreover, differential counts showed that hUCB-MSC treatment has regenerative effects on white blood cells, lymphocytes, and monocytes compared with the irradiated group. Treatment with hUCB-MSCs or G-CSF significantly increased immunoreactivity of Ki-67 until 3 weeks after total body irradiation. However, at 3 weeks, the number of Ki-67 immunoreactive cells significantly increased in the hUCB-MSCs-treated group compared with the G-CSF-treated group. Furthermore, hUCB-MSC treatment significantly modulated plasma levels of the hematopoietic cytokines Flt-3L and TGF-β1, whereas G-CSF treatment failed to decrease the plasma Flt-3L levels at 2 weeks after irradiation. Based on the differences in circulating blood cell reconstitution and cell density of bone marrow, the authors suggest that MSC treatment is superior to G-CSF treatment for hematopoietic reconstitution following sublethal dose radiation exposure.

The construction, analysis and legacy of the radiation chimaera

By August 1945 Jacobson and his associates in Chicago had observed that following the ingestion of 89Sr the murine spleen exerted a beneficial effect, which they attributed to a 'radiation protection factor' that could not be isolated from the spleen but which could be transferred to irradiated recipients in splenic implants or in suspensions of spleen cells. In 1952 Congdon, Lorenz and Uphoff at Bethesda successfully used bone marrow cells to protect mice against the lethal effects of whole body irradiation and recognized the possibility that protection could be due to the transplantation of blood cell precursors. This possibility was endorsed by the investigations of Barnes and Loutit in Harwell, which revealed that the radiation protection factor was antigenic and that it was preserved under conditions which were known to sustain living cells but not under conditions which were adequate for the preservation of unstable chemical compounds. Within four years the use of markers proved that donor bone marrow cells repopulate the medullary cavities of irradiated mice. The radiation chimaera had been constructed and the stage was set for three decades of research and development during which the transplantation of blood cell precursors was established as a routine treatment for impaired haematopoiesis, a unique model for the study of stem cell populations was analysed and the generation of a rich legacy was commenced.

Incidence of tissue toxicities in gamma ray and fission neutron-exposed mice treated with Amifostine

Purpose: To determine the effects of Amifostine or WR-151327 on the incidence of lethal and non-lethal toxicities in a large cohort of mice exposed to γ-ray or fission-spectrum neutron radiation.Methods: To analyze data from 4000 B6CF1 mice which received a single whole body irradiation (WBI) with 206 cGy or 417 cGy cobalt-60 gamma rays or 10 cGy or 40 cGy of fission-spectrum neutrons (average energy 0.85 MeV) produced by the Janus reactor at Argonne National Laboratory. In the neutron cohort, Amifostine, WR-151327, saline or nothing was injected once, intraperitoneally, 30 minutes before irradiation. In the cobalt-60 cohort, WR-151327 was omitted from the same protocol. At the time of natural death, tissue toxicities found in these mice were recorded, and these records were analyzed. While all previous studies focused on the modulation of life shortening effects of WBI by Amifostine, in this study we calculated changes in the frequencies of 59 tissue toxicities and changes in the total number of toxicities per animal.Results: Amifostine protected against specific non-tumor pathological complications (67% of the non-tumor toxicities induced by gamma irradiation, 31% of the neutron induced specific toxicities), as well as specific tumors (56% of the tumor toxicities induced by gamma irradiation, 25% of the neutron induced tumors). Amifostine also reduced the total number of toxicities per animal for both genders in the gamma ray exposed mice and in males in the neutron exposed mice.Conclusions: Amifostine was protective against many, but not all, tissue toxicities caused by WBI gamma and neutron irradiation.

Effect of high-dose, fractionated local irradiation on MNU-induced carcinogenesis in the rat mammary gland.

The effect on chemical carcinogenesis in the mammary gland of high-dose fractionated, local irradiation, as is used in the treatment of human breast cancer, was examined in a rat model of this disease process. For this purpose, a highly reproducible method was employed for administering a therapeutic dose and fractionation schedule via an anterior portal to a single mammary gland chain of rats in a manner that minimized whole body irradiation. This approach offers significant advantages over whole body irradiation techniques previously used for investigations of radiation-mediated effects on the carcinogenic process. Among the advantages are that higher doses of radiation can be administered to the target tissue with minimal side effects and that the contralateral mammary gland chain can serve as a 'within animal control'. When this approach was used to study the effect of high-dose fractionated radiation on the risk of development of mammary cancer in rats given 1-methyl-1-nitrosourea prior to radiation, an enhanced tumorigenic response was observed that greatly exceeded the response resulting from either radiation or carcinogen administered alone. This result was unanticipated, based on data from animal studies of the effects of whole body irradiation on mammary tumor development and the outcome of clinical series. Possible reasons for the discrepancy are presented.

Early biological effects of whole body irradiation on rat lungs.

The influence of whole-body irradiation (WBI) with 4, 8 and 15 Gy ionizing radiation upon some biochemical indices in the bronchoalveolar lavage fluid (BALF) of rat lungs was studied. It was established that lactate dehydrogenase (LDH), alkaline phosphatase, (APH) and acid phosphatase (AcPH) activities show a dose-dependent decrease on the day 1 and day 5 after the irradiation. A similar trend was observed in the total protein content on the day 1. Angiotensin converting enzyme (ACE) activity was increased on the day 1 in the groups irradiated with 8 Gy and 15 Gy in comparison with the controls (190,2% and 187,5%, respectively). It was concluded that WBI decreases LDH, APH and AcPH levels in the lung cells, which secrete them into bronchoalveolar spaces. An irradiation with 8 Gy and 15 Gy WBI provokes an early damage on cytoplasmic membranes of the endothelial cells in lung capillars. It was considered that the bronchoalveolar lavage can find a more wide application for evaluation of the biological effect of ionizing radiation in lungs.

Radiation Enhances Silica Translocation to the Pulmonary Interstitium and Increases Fibrosis in Mice

The effects of whole body irradiation (WBR) on particle clearance and the development of pulmonary fibrosis have been investigated. Using carbon, clearance is accomplished by polymorphonuclear leukocytes (PMN) and alveolar macrophages (AM), and only a few particles reach the interstitum. However, in preirradiated mice, the usual eflux of inflammatory cells is much delayed so that more free carbon remains in the alveoli, and by 1 week, many particles cross the epithelium to be phagocytized by interstitial macrophages. Carbon is found in the peribronchiolar interstitium 6 months later with no evidence of fibrosis. In the present study, mice received 1 mg silica intratracheally 2 days after 6.5 Gy WBR when the white blood cell count was low. A much-reduced AM and PMN response was found in the following 2 weeks compared to the reaction to silica alone, and many silica particles reached interstitial macrophages. In this case, macrophage activation by silica was associated with fibroblast proliferation, and by 16 weeks, much more pulmonary fibrosis was produced than after silica or irradiation only. This was measured biochemically and correlated with a large increase in retained silica in the irradiation-silica group. The results indicate that radiation inhibits the inflammatory response to particle instillation, resulting in greater translocation of free particles to the pulmonary interstitium. In the case of silica, the greater, prolonged interaction with interstitial macrophages leads to a much exaggerated fibrotic reaction.

Radiation enhances silica translocation to the pulmonary interstitium and increases fibrosis in mice.

The effects of whole body irradiation (WBR) on particle clearance and the development of pulmonary fibrosis have been investigated. Using carbon, clearance is accomplished by polymorphonuclear leukocytes (PMN) and alveolar macrophages (AM), and only a few particles reach the interstitum. However, in preirradiated mice, the usual eflux of inflammatory cells is much delayed so that more free carbon remains in the alveoli, and by 1 week, many particles cross the epithelium to be phagocytized by interstitial macrophages. Carbon is found in the peribronchiolar interstitium 6 months later with no evidence of fibrosis. In the present study, mice received 1 mg silica intratracheally 2 days after 6.5 Gy WBR when the white blood cell count was low. A much-reduced AM and PMN response was found in the following 2 weeks compared to the reaction to silica alone, and many silica particles reached interstitial macrophages. In this case, macrophage activation by silica was associated with fibroblast proliferation, and by 16 weeks, much more pulmonary fibrosis was produced than after silica or irradiation only. This was measured biochemically and correlated with a large increase in retained silica in the irradiation-silica group. The results indicate that radiation inhibits the inflammatory response to particle instillation, resulting in greater translocation of free particles to the pulmonary interstitium. In the case of silica, the greater, prolonged interaction with interstitial macrophages leads to a much exaggerated fibrotic reaction.

Short- and Long-Term Effects of Whole-Body Irradiation with Fission Neutrons or X Rays on the Thymus in CBA Mice

Young adult (6 weeks old) female CBA mice were exposed to whole-body irradiation with either 2.5-Gy fast fission neutrons of 1 MeV mean energy or 6.0-Gy 300 kVp X rays at centerline dose rates of 0.1 and 0.3 Gy/min, respectively. The weight of spleen and animal and the weight, cellularity, and histological structure of the thymus were studied at different times after irradiation. Thymic recovery after whole-body irradiation showed a biphasic pattern with minima at 5 and 21 days after irradiation and peaks of regeneration at Days 14 and 42 after X irradiation or at Days 14 and 70 after neutron irradiation. After the second phase of recovery, a marked decrease in relative thymus weight and cellularity was observed, which lasted up to at least 250 days after irradiation. Splenic recovery showed a monophasic pattern with an overshoot on Day 21 after irradiation. After neutron irradiation a late decrease in relative spleen and animal weight was observed. The observed late effects on thymus and spleen weight and thymus cellularity are discussed in terms of a persistent defect in the bone marrow.

Neoplasia in adoptively immunosuppressed rats. A possible model for tumorigenesis in transplant recipients.

An extremely high incidence of malignant tumors was observed in groups of rats that had previously been exposed to whole body irradiation, grafted with allogeneic tissue, and injected with lymphocytes capable of specifically suppressing the rejection of the grafted tissue. Neoplasia in these adoptively immunosuppressed rats had features in common with that in therapeutically immunosuppressed transplant recipients. Increased tumor incidence could not be accounted for on the basis of the effects of whole body irradiation or failure of immune surveillance, nor could it be a direct effect of lymphoid tissue stimulation. It is suggested that cell mediated suppressor responses play a critical role in tumorigenesis. The mechanism of this is not simply direct stimulation of lymphoid tissue proliferation.

The Effects of Whole-body Irradiation on the Serum Levels and Kinetics of Thyroid Hormones in Rats

The Effects of Whole-body Irradiation on the Serum Levels and Kinetics of Thyroid Hormones in Rats

The Effects of Whole-body Irradiation on the Serum Levels and Kinetics of Thyroid Hormones in Rats

The effects of a single whole-body dose of X-rays on the serum levels and kinetics of thyroid hormones in rats were studied. The influence of radiation-induced anorexia was monitored by using pair fed control groups. A dose of 800 rad caused a reduction in T4 levels and 750 rad had a similar effect on T3; in each case the control group showed a smaller reduction. The kinetic results indicated that, in the control groups, the early reduction in hormone concentrations was caused, by a change in the distribution of the hormone; however, the continuing reduction in hormone levels in the irradiated rats appeared to results from decreased production. The results suggest that the thyroid system may play an active part in the early metabolic changes which follow whole-body irradiation.

The Effects of Whole-body Irradiation on the Serum Levels and Kinetics of Thyroid Hormones in Rats

The Effects of Whole-body Irradiation on the Serum Levels and Kinetics of Thyroid Hormones in Rats

Immunological effects of irradiation: Waiting for a model

Decreased resistance to pathogens, which is an effect of ionizing radiations that is well documented in several animal species, is largely mediated by impairment of the specific immune response. The effects of irradiation on the antibody response have been extensively investigated during the past several decades. It has been established that the antibody response is depressed when the antigen is injected shortly before or immediately after irradiation. Recovery of the response in animals immunized after sublethal irradiation starts after about 1 week and may be complete 2 months after irradiation. If animals are immunized a few or several days before radiation exposure, some parameters of the antibody response are unaffected while others may display lower or higher values than normal, depending on the nature and physical form of the antigen. Recent studies have described the effects of whole-body irradiation on antibody affinity. Since this antibody property affects the stability of immune complexes and, therefore, the antibody's ability to neutralize viruses and toxins, affinity was felt to be of importance to counteract infections in irradiated animals. Antibody affiinity was found up to 20 times greater in irradiated than in control mice when antigen was injected 1–5 days before or 2 hr-8 weeks after a sublethal dose of X-rays. Recovery profiles of mitotic responses of spleen cells to PHA, ConA, or LPS suggest that the enhancement of antibody affinity in irradiated mice could result from a relative lack of suppressor T cells. Dysfunctions of the immune system of irradiated animals can be attributed to alterations of the populations of immunologically competent cells. Unlike auxiliary cells, lymphocytes are extremely sensitive to ionizing radiations. Subpopulations of T and B lymphocytes appear to have different radiosensitivities and to develop with different efficiencies in irradiated animals. B cells seem to be more radiosensitive and to recover faster than T cells. The radiosensitivity of lymphocytes decreases with differentiation from precursor to effector cells. However, like activated cytoxic cells, primed helper cells include very radiosensitive subpopulations.

Effects of whole body irradiation in mice treated with C. parvum

We have investigated the effect of whole body irradiation (WBI) upon the survival of Corynebacterium parvum ( C. parvum)-treated CBA mice. Applied to mice 7 days after C. parvum WBI with 350–950 rad of X-ray killed more C. parvum-treated than -untreated mice. The number of endogenous hematopoietic colonies determined either at 9 days of irradiation or at the time of death of mice was greater in C. parvum-treated mice than in mice irradiated only. Using the exogenous spleen colony assay, it was found that CFUs from the spleen of mice treated with C. parvum were more sensitive to irradiation than the CFUs from the spleen of normal mice, Leucopenia caused by irradiation was equally severe in both groups of mice. However, a decrease in the number of erythrocytes was more pronounced in mice treated with C parvum and irradiation than in those given irradiation alone. Possible reasons for the increased radiosensitivity of C. parvum-treated mice as well as the relevance of these findings to tumor immunotherapy are discussed.

The Effects of Whole-Body Irradiation on Survival and Erythropoiesis of Rana catesbeiana Tadpoles

JUST, J. J., AND SPERKA, R. The Effects of Whole-Body Irradiation on Survival and Erythropoiesis of Rana catesbeiana Tadpoles. Radiat. Res. 69, 258-266 (1977). Rana catesbeiana larvae were exposed to various amounts of whole-body X radiation ranging from 500 to 20,000 R. Young larval stages are more resistant to irradiation damage than are older stages. Of young animals, 50% survive exposures of 1000 R or more for longer than 21 days, while all animals undergoing metamorphic climax die after the same exposures within 16 days. Normal animals exposed to X radiation do not show a change in erythropoiesis as measured by circulating levels of red blood cells. When animals were made anemic by phenylhydrazine administration, it was possible to demonstrate for the first time an effect of irradiation on amphibian erythropoiesis.

Experimental bone marrow transplantation

Attempts to transfer bone marrow met with little success before the 1940's. It had still to be realized, that bone marrow differentiated from transplantable stem ceils, which engraft only in recipients needing stem cells. Also, the importance of histocompatibility between donor and recipient was not recognized. One thing that was puzzling, due to its simplicity rather than its complexity, was the method of administering bone marrow: Earlier applications of bone marrow per os, by intramedullary or intraperitoneal injections were finally replaced by the intravenous route (for historical review see [1], [10]). In the 1950's, when the fear of nuclear warfare had mobilized biologists in the United States to study systematically the effects of whole body irradiation, Loren z et al. [2] reported in 1951 that lethally irradiated mice could be saved by the intravenous injection of bone marrow from other mice, and not only by shielding the spleen of the irradiated mice as Jacobsen et al. [5] had demonstrated shortly before. Experimental data by Barnes et al. from Harwell in England [4] supported the "cellular hypothesis" arising from Loren z' observation of a cell-born repopulation of the bone marrow cavity. In contrast the "humoral hypothesis" postulated factors in cell-free homogenates of spleen or bone-inducing hemopoietic regeneration after irradiation [3], [5]. The final confirmation of successful bone marrow transplantation was the proof in 1956 of a persistence in the marrow recipient of mouse [6] or rat [7,8] donor cells, which could be distinguished by cytogenetic, histochemical or serological techniques. When highly inbred strains of mice became available it was recognized that bone marrow could be easily grafted only within the same strain. Experiments with irradiated mice which had been given marrow from foreign, histoincompatible strains [9,11,13] remained less successful. While the laws of transplantation were explored on the basis of skinor tumor graft rejection by the host, researchers attempting bone marrow transplantations realized that they were dealing additionally with the reverse situation: an immunocompetent graft "rejecting" its host.

Effects of Whole-Body Irradiation and Hormones on Drug Metabolism in the Liver Endoplasmic Reticulum

KNOTT, J. C. A., AND WILLS, E. D. Effects of Whole-Body Irradiation and Hormones on Drug Metabolism in the Liver Endoplasmic Reticulum. Radiat. Res. 53, 65-76 (1973). The rate of oxidative demethylation of aminopyrine by preparations of microsomes from male rat livers decreased following whole-body irradiation, reaching a minimum, of 25% of the control value, on the 4th and 5th days after 850 rads. Oxidative demethylation in preparations of microsomes from female rats or male or female mice was unaffected by this dose of irradiation. The decreased rate in male rats was caused mainly by an increase of the K. for the reaction from 0.52 to 1.60 mM. The rate of hydroxylation of biphenyl in the male rat liver was also depressed by whole-body irradiation to a similar extent as oxidative demethylation. Cytochrome P450 concentration in the microsomes was unaffected by irradiation, but NADPH cytochrome c reductase activity was depressed.

Effect of Whole-Body Irradiation and Puromycin on Hydrolytic Enzyme Activation in Regenerating Rat Liver

The effects of whole-body gamma irradiation, which blocks DNA synthesis, and puromycin, a protein synthesis inhibitor, on total organ activities of three acid hydrolases of regenerating, radiosensitive rat liver, were studied. Doses of 1000 or 10,000 rads, given immediately or 6 hours after subtotal hepatectomy, failed to prevent the twofold increase in total organ activities normally elicited by partial hepatectomy. Puromycin, injected every 3 hours in amounts large enough to inhibit protein synthesis, was also not effective. The observed rise of total organ hydrolase activities in regenerating liver may be due to selective removal of natural inhibitors of the enzymes, or to some form of enzyme activation. The process is not sensitive to gamma irradiation or protein synthesis arrest.

Comparison of autologous marrow injection to shielding in lethal irradiation of the mouse.

Shielding of small portions of the hematopoietic system provides protection against the lethal effects of whole-body irradiation in the midlethal dose range. Transfusion of either whole blood or transplantation of hematopoietic tissues protects to some degree in every mammalian species studied.Manipulation of the radiation dose, time of transplant and recipient treatment with immune suppressors leads to some success in transplants between species. The probability of acceptance of an allograft is inversely related to the number of histocompatibility differences. Hence, in identical twins with no antigenic differences there should be 100% takes. Several investigators (1-4) have followed Atkinson (5) in attempting transplants between a normal individual and his whole-body irradiated leukemic identical twin. A logical extension of identical twin donor-recipient matching is the autologous transplant. The patient serves as donor and recipient with an interim treatment of radio or chemotherapy. This method has b...

Growth of metastases from P-388 sarcoma in the rat followig whole body irradiation.

The growth of an allogeneic rapidly growing and metastasizing sarcoma (P-388) in the rat is described. Quantitative and kinetic data are provided concerning the growth of individual metastases produced in three principal regional lymph node drainage groups, and are compared with growth of the primary tumour of origin in muscle; the incidence of pulmonary metastases is also given. The effects on growth of metastases and primaries produced by sublethal whole body irradiation (WBI) before inoculations of 10-10(8) tumour cells are described.Growth of P-388 sarcoma in unirradiated recipients (ED(50) ≃ 5 × 10(3) cells) obeyed the linear growth law proposed by the Mayneord model for tumour growth, but in irradiated recipients (ED(50) < 10 cells) early growth of primaries and metastases approximated more closely to an exponential rate of growth.The ratio M/P of weight of metastases (M) to weight of primary tumour of origin (P) increased at a linear rate with age (t) of tumour, and gave the same slope namely, 0·029 for pelvic node metastases) in unirradiated rats inoculated with a large (10(6)-10(7)) number of cells as in irradiated rats. The slope was decreased to 0·014 for pelvic node metastases in unirradiated rats challenged with fewer (10(4)) cells but not in irradiated recipients. It is postulated that the effects of WBI on growth of metastases are confined to causing a suppression of immunity, and that WBI does not affect tumour spread significantly through other mechanisms.In immunologically competent rats the phenomena of sequestrated progressive growth of isolated metastases in lymph nodes and of a chronic nonprogressive enlargement of nodes in which persistent tumour growth and destruction occurred side by side are described, and effects on prognoses and clinical behaviour, are discussed.The P-388 tumour is considered of value in quantitative and kinetic experimental studies of metastases, and particularly those in which the role of immunity needs to be assessed and measured to avoid confusion with other factors or agents which might affect the spread and growth of metastases.