Biomedical subjects

Michael J Pecaut

Publications and source records attributed to Michael J Pecaut.

15 recordsLinked to original sources

PubMed2006

Acute effects of iron-particle radiation on immunity. Part II: Leukocyte activation, cytokines and adhesion.

The effects of high-linear energy transfer (LET) radiation on immune function have not been clearly established. The major goal of this study was to evaluate leukocyte responses after whole-body exposure to high-LET radiation. C57BL/6 mice were exposed to 0, 0.5, 2 and 3 Gy (56)Fe(26+) particles (1055 MeV/nucleon, 148.2 keV/microm) and killed humanely 4 days after exposure. Spontaneous synthesis of DNA in blood and spleen cells was increased significantly in groups receiving either 2 or 3 Gy (P < 0.001). In contrast, a significant depression in the response of T lymphocytes to phytohemagglutinin (PHA) and concanavalin A (ConA) was noted (P < 0.005); the response to lipopolysaccharide (LPS), a B-cell mitogen, was similar among groups. A cytometric bead array assay revealed that the level of tumor necrosis factor alpha (Tnfa) secreted by splenocytes increased significantly with increasing (56)Fe-particle dose (P < 0.05); interferon gamma, interleukin2 (Il2), Il4 and Il5 were unaffected. Flow cytometry analysis showed that 2 and 3 Gy markedly reduced splenic mononuclear cells expressing the activation markers CD25 and CD71, both with and without the T-cell marker CD3 (P < 0.05); proportions also varied significantly. Similar patterns were noted in mononuclear and granular cells with adhesion markers CD11b and, to a lesser extent, CD54 (P < 0.05). The results show that a single, acute exposure to high-LET radiation induced changes that can profoundly alter leukocyte functions. The implications of the data are discussed in relation to low-LET radiation, altered gravity, and space flight.

Animals↗

PubMed2006

Acute effects of iron-particle radiation on immunity. Part I: Population distributions.

Health risks due to exposure to high-linear energy transfer (LET) charged particles remain unclear. The major goal of this study was to confirm and further characterize the acute effects of high-LET radiation ((56)Fe(26)) on erythrocyte, thrombocyte and leukocyte populations in three body compartments after total-body exposure. Adult female C57BL/6 mice were irradiated with total doses of 0, 0.5, 2 and 3 Gy and killed humanely 4 days later. Body and organ masses were determined and blood, spleen and bone marrow leukocytes were evaluated using a hematology analyzer and flow cytometry. Spleen and thymus (but not body, liver and lung) masses were significantly decreased in a dose-dependent manner. In general, red blood cell (RBC) counts and most other RBC parameters were depressed with increasing dose (P < 0.05); the major exception was an increase in cell size at 0.5 Gy. Platelet numbers and volume, total white blood cell counts, and all three major types of leukocytes also decreased (P < 0.05). Lymphocyte populations in blood and spleen exhibited variable degrees of susceptibility to (56)Fe-particle radiation (B > T > NK and T cytotoxic > T helper cells). In the bone marrow, leukocytes with granulocytic, lymphocytic ("dim" and "bright"), and monocytic characteristics exhibited proportional variations at the higher radiation doses in the expression of CD34 and/or Ly-6A/E. The data are discussed in relation to our previous investigations with iron ions, other forms of radiation, and space flight in this same animal model.

Animals↗

PubMed2005

HZE radiation and dopaminergic modification of startle and prepulse inhibition in mice.

C57BL/6 mice were exposed to 5 Gy (28)Si or (56)Fe particle radiation in order to explore the immediate or short-latency effect of exposure to high energy (HZE) particle radiation on dopaminergic modification of acoustic startle and prepulse inhibition. The radiation is representative of the type which would be encountered as galactic cosmic rays during long-duration space flight. The acoustic startle response was elicited with 120 dB white noise and prepulse inhibition of the startle response was produced with 79 dB and 86 dB stimuli presented with a 125 ms onset asynchrony. Startle reactivity was inhibited by (56)Fe radiation but not by (28)Si particles. Apomorphine (3 mg/kg) produced a general inhibition of startle reactivity while haloperidol (1 mg/kg) facilitated it. Apomorphine disrupted prepulse inhibition, but only in animals which were not exposed to radiation. Both (56)Fe and (28)Si radiation exposure attenuated the disruption of prepulse inhibition induced by apomorphine. In contrast, the facilitation of prepulse inhibition induced by haloperidol was not modified by radiation. These data are consistent with a short-latency disruption of dopaminergic systems by HZE particle radiation. We speculate that this disruption may occur as a restriction in the capacity of the dopaminergic system.

Acoustic Stimulation↗

PubMed2004

Hypergravity-induced immunomodulation in a rodent model: hematological and lymphocyte function analyses.

The major purpose of this study was to quantify hypergravity-induced changes in erythrocyte and thrombocyte characteristics, spontaneous and mitogen-induced lymphoblastogenesis, and capacity of splenocytes to secrete immunoregulatory cytokines. C57BL/6 mice were subjected to chronic 1, 2, and 3 G; subsets were euthanized after 1, 4, 7, 10, and 21 days of centrifugation. Erythrocyte counts, hematocrit, and hemoglobin were significantly reduced by day 21 in both centrifuged groups. Hemoglobin concentration and volume per red blood cell were generally low, but an early, transient spike above normal was noted in thrombocyte counts in the 3-G group. Fluctuations above and below normal in blood and spleen cell spontaneous blastogenesis were dependent on the length of centrifugation time and not on the level of gravity. Depression in splenocyte responses to phytohemagglutinin and lipopolysaccharide due to gravity were noted when the data were expressed as stimulation indexes. Cytokine production by spleen cells was primarily affected during the first week of centrifugation: IL-2, IL-4, and tumor necrosis factor-alpha increased, whereas interferon-gamma decreased. These findings, although not identical to those reported for spaceflight, indicate that altered gravity can influence both hematological and functional variables that may translate into serious health consequences during extended missions.

Animals↗

PubMed2004

The effects of low-dose, high-LET radiation exposure on three models of behavior in C57BL/6 mice.

To investigate the behavioral consequences of exposure to whole-body irradiation such as might occur for astronauts during space flight, female C57BL/6 mice were exposed to 0, 0.1, 0.5 or 2 Gy accelerated iron ions (56Fe, Z = 26, beta = 0.9, LET = 148.2 keV/microm) of 1 GeV per nucleon using the Alternating Gradient Synchrotron at the Brookhaven National Laboratory. Animal testing began 2 weeks after exposure and continued for 8 weeks. Under these conditions, there were few significant effects of radiation on open-field, rotorod or acoustic startle activities at any of the times examined. The lack of radiation effects in these behavioral models appears to offer reassurance to NASA mission designers. These results suggest that there may be negligible effects of HZE radiation on many behaviors during a 2-8-week period immediately after radiation.

Animals↗

PubMed2003

Genetic models in applied physiology: selected contribution: effects of spaceflight on immunity in the C57BL/6 mouse. I. Immune population distributions.

There are several aspects of the spaceflight environment that may lead to changes in immunity: mission-related psychological stress, radiation, and changes in gravity. On December 5, 2001, the space shuttle Endeavor launched for a 12-day mission to examine these effects on C57BL/6 mice for the first time. On their return, assays were performed on the spleen, blood, and bone marrow. In response to flight, there were no significant differences in the general circulating leukocyte proportions. In contrast, there was an increase in splenic lymphocyte percentages, with a corresponding decrease in granulocytes. There was an overall shift in splenic lymphocytes away from T cells toward B cells, and a decrease in the CD4-to-CD8 ratios due to a decrease in T helpers. In contrast, there were proportional increases in bone marrow T cells, with decreases in B cells. Although the blast percentage and count were decreased in flight mice, the CD34(+) population was increased. The data were more consistent with a shift in bone marrow populations rather than a response to changes in the periphery. Many of the results are similar to those using other models. Clearly, spaceflight can influence immune parameters ranging from hematopoiesis to mature leukocyte mechanisms.

Animals↗

PubMed2003

Long-term effects of low-dose proton radiation on immunity in mice: shielded vs. unshielded.

BACKGROUND: Outside the protection of the terrestrial environment, astronauts on any long-term missions will unavoidably be exposed to fields of charged particle radiation dominated by protons. These fields and their biological risks are modified in complex ways by the presence of protective shielding. METHODS: To examine the long-term effects of space-like proton exposures on immune status, we treated female C57BL/6 mice with 3 or 4 Gy of 250 MeV monoenergetic protons or the complex space-like radiation field produced after 250 MeV protons are transported through 15 g x cm(-2) aluminum shielding. The animals were euthanized 122 d post-irradiation and lymphocyte phenotypes, hematological parameters, and lymphocyte blastogenesis were characterized. RESULTS: There were significant dose-dependent decreases in macrophage, CD3+/CD8+ T, NK, platelet, and red blood cell populations, as well as low hematocrit and hemoglobin levels. In contrast, dose-dependent increases in spontaneous, but not mitogen-induced, blastogenesis were noted. The differences in dose composition between pristine and shielded proton fields did not lead to significant effects in most measures, but did result in significant changes in monocyte and macrophage populations and spontaneous blastogenesis in the spleen. CONCLUSIONS: The data indicate that whole body exposure to proton radiation at doses of the order of large solar particle events or clinical treatment fractions may have long-term effects on immune system status.

Animals↗

PubMed2002

Genetic models in applied physiology: selected contribution: effects of spaceflight on immunity in the C57BL/6 mouse. II. Activation, cytokines, erythrocytes, and platelets.

This portion of the study quantified the effects of a 12-day space shuttle mission (Space Transport System-108/UF-1) on body and lymphoid organ masses, activation marker expression, cytokine secretion, and erythrocyte and thrombocyte characteristics in C57BL/6 mice. Animals in flight (Flt group) had 10-12% lower body mass compared with ground controls housed either in animal enclosure modules or under standard vivarium conditions (P < 0.001) and the smallest thymus and spleen masses. Percentages of CD25(+) lymphocytes, CD3(+)/CD25(+) T cells, and NK1.1(+)/CD25(+) natural killer cells from Flt mice were higher compared with both controls (P < 0.05). In contrast, CD71 expression was depressed in the Flt and animal enclosure module control mice compared with vivarium control animals (P < 0.001). Secretion of interferon-gamma, IL-2, and IL-4, but not tumor necrosis factor-alpha and IL-5, by splenocytes from Flt mice was decreased relative to either one or both ground controls (P < 0.05). Flt mice also had high red blood cell and thrombocyte counts compared with both sets of controls; low red blood cell volume and distribution width, percentage of reticulocytes, and platelet volume were also noted (P < 0.05) and were consistent with dehydration. These data indicate that relatively short exposure to the spaceflight environment can induce profound changes that may become significant during long-term space missions.

Animals↗

PubMed2002

Dose and dose rate effects of whole-body proton irradiation on leukocyte populations and lymphoid organs: part I.

The goal of part I of this study was to evaluate the effects of whole-body proton irradiation on lymphoid organs and specific leukocyte populations. C57BL/6 mice were exposed to the entry region of the proton Bragg curve to total doses of 0.5 gray (Gy), 1.5 Gy, and 3.0 Gy, each delivered at a low dose rate (LDR) of 1 cGy/min and high dose rate (HDR) of 80 cGy/min. Non-irradiated and 3 Gy HDR gamma-irradiated groups were included as controls. At 4 days post-irradiation, highly significant radiation dose-dependent reductions were observed in the mass of both lymphoid organs and the numbers of leukocytes and T (CD3(+)), T helper (CD3(+)/CD4(+)), T cytotoxic (CD3(+)/CD8(+)), and B (CD19(+)) cells in both blood and spleen. A less pronounced dose effect was noted for natural killer (NK1.1(+) NK) cells in spleen. Monocyte, but not granulocyte, counts in blood were highly dose-dependent. The numbers for each population generally tended to be lower with HDR than with LDR radiation; a significant dose rate effect was found in the percentages of T and B cells, monocytes, and granulocytes and in CD4(+):CD8(+) ratios. These data indicate that mononuclear cell response to the entry region of the proton Bragg curve is highly dependent upon the total dose and that dose rate effects are evident with some cell types. Results from gamma- and proton-irradiated groups (both at 3 Gy HDR) were similar, although proton-irradiation gave consistently lower values in some measurements.

Animals↗

PubMed2002

Dose and dose rate effects of whole-body proton-irradiation on lymphocyte blastogenesis and hematological variables: part II.

The goal of part II of this study was to evaluate functional characteristics of leukocytes and circulating blood cell parameters after whole-body proton irradiation at varying doses and at low- and high-dose-rates (LDR and HDR, respectively). C57BL/6 mice (n=51) were irradiated and euthanized at 4 days post-exposure for assay. Significant radiation dose- (but not dose-rate-) dependent decreases were observed in splenocyte responses to T and B cell mitogens when compared to sham-irradiated controls (P<0.001). Spontaneous blastogenesis, also significantly dose-dependent, was increased in both blood and spleen (P<0.001). Red blood cell counts, hemoglobin concentration, and hematocrit were decreased in a dose-dependent manner (P<0.05), whereas thrombocyte numbers were only slightly affected. Comparison of proton- and gamma-irradiated groups (both receiving 3 Gy at HDR) showed a higher level of spontaneous blastogenesis in blood leukocytes and a lower splenocyte response to concanavalin A following proton irradiation (P<0.05). There were no dose rate effects. Collectively, the data demonstrate that the measurements in blood and spleen were largely dependent upon the total dose of proton radiation and that an 80-fold difference in the dose rate was not a significant factor. A difference, however, was found between protons and gamma-rays in the degree of change induced in some of the measurements.

Animals↗

PubMed2002

Total-body irradiation with high-LET particles: acute and chronic effects on the immune system.

Although the immune system is highly susceptible to radiation-induced damage, consequences of high linear energy transfer (LET) radiation remain unclear. This study evaluated the effects of 0.1 gray (Gy), 0.5 Gy, and 2.0 Gy iron ion (56Fe(26)) radiation on lymphoid cells and organs of C57BL/6 mice on days 4 and 113 after whole body exposure; a group irradiated with 2.0 Gy silicon ions (28Si) was euthanized on day 113. On day 4 after 56Fe irradiation, dose-dependent decreases were noted in spleen and thymus masses and all major leukocyte populations in blood and spleen. The CD19(+) B lymphocytes were most radiosensitive and NK1.1(+) natural killer (NK) cells were most resistant. CD3(+) T cells were moderately radiosensitive and a greater loss of CD3(+)/CD8(+) T(C) cells than CD3(+)/CD4(+) T(H) cells was noted. Basal DNA synthesis was elevated on day 4, but response to mitogens and secretion of interleukin-2 and tumor necrosis factor-alpha were unaffected. Signs of anemia were noted. By day 113, high B cell numbers and low T(C) cell and monocyte percents were found in the 2.0 Gy 56Fe group; the 2.0 Gy 2)Si mice had low NK cells, decreased basal DNA synthesis, and a somewhat increased response to two mitogens. Collectively, the data show that lymphoid cells and tissues are markedly affected by high linear energy transfer (LET) radiation at relatively low doses, that some aberrations persist long after exposure, and that different consequences may be induced by various densely ionizing particles. Thus simultaneous exposure to multiple radiation sources could lead to a broader spectrum of immune dysfunction than currently anticipated.

Animals↗

PubMed2002

Behavioral consequences of radiation exposure to simulated space radiation in the C57BL/6 mouse: open field, rotorod, and acoustic startle.

Two experiments were carried out to investigate the consequences of exposure to proton radiation, such as might occur for astronauts during space flight. C57BL/6 mice were exposed, either with or without 15-g/cm2 aluminum shielding, to 0-, 3-, or 4-Gy proton irradiation mimicking features of a solar particle event. Irradiation produced transient direct deficits in open-field exploratory behavior and acoustic startle habituation. Rotorod performance at 18 rpm was impaired by exposure to proton radiation and was impaired at 26 rpm, but only for mice irradiated with shielding and at the 4-Gy dose. Long-term (>2 weeks) indirect deficits in open-field activity appeared as a result of impaired experiential encoding immediately following exposure. A 2-week recovery prior to testing decreased most of the direct effects of exposure, with only rotorod performance at 26 rpm being impaired. These results suggest that the performance deficits may have been mediated by radiation damage to hippocampal, cerebellar, and possibly, forebrain dopaminergic function.

Animals↗

PubMed2002

Hypergravity-induced immunomodulation in a rodent model: lymphocytes and lymphoid organs.

The major goal of this study was to quantify changes in lymphoid organs and cells over time due to centrifugation-induced hypergravity. C57BL/6 mice were exposed to 1, 2 and 3 G and the following assays were performed on days 1, 4, 7, 10, and 21: spleen, thymus, lung, and liver masses; total leukocyte, lymphocyte, monocyte/macrophage, and granulocyte counts; level of splenocyte apoptosis; enumeration of CD3+ T, CD3+/CD4+ T helper, CD3+/CD8+ T cytotoxic, B220+ B, and NK1.1+ natural killer cells; and quantification of cells expressing CD25, CD69, and CD71 activation markers. The data show that increased gravity resulted in decreased body, spleen, thymus, and liver, but not lung, mass. Significant reductions were noted in all three major leukocyte populations (lymphocytes, granulocytes, monocyte/macrophages) [correction of macrphages] with increased gravity; persistent depletion was noted in blood but not spleen. Among the various lymphocyte populations, the CD3+/CD8+ T cells and B220+ B cells were the most affected and NK1.1+ NK cells the least affected. Overall, the changes were most evident during the first week, with a greater influence noted for cells in the spleen. A linear relationship was found between some of the measurements and the level of gravity, especially on day 4. These findings indicate that hypergravity profoundly alters leukocyte number and distribution in a mammalian model and that some aberrations persisted throughout the three weeks of the study. In certain cases, the detected changes were similar to those observed after whole-body irradiation. In future investigations we hope to combine hypergravity with low-dose rate irradiation and immune challenge.

Animals↗

PubMedDate not supplied

"Out-of-field" effects of head-localized proton irradiation on peripheral immune parameters.

The heads of Sprague-Dawley rats were irradiated with protons to total doses of 1.5, 3 and 4 Gy and euthanized 9-10 days later. Significant dose-dependent decreases were noted in thymus mass. Lymphocyte and platelet numbers were significantly reduced in blood. Flow cytometric analysis of blood and spleen showed that CD3+ T, CD3+/CD4+ TH, and CD3+/CD8+ TC cell numbers were low and proportions were significantly altered by radiation. CD4:CD8 ratios and CD45R+ B lymphocytes were unaffected. Spontaneous blastogenesis of blood and spleen leukocytes was significantly increased by radiation. Plasma TGF-beta 1 level in irradiated rats was consistently, but not significantly, higher than in non-irradiated animals. T and B cell proportions in lymph nodes from irradiated animals were similar to non-irradiated controls. Bone marrow from all irradiated groups had high CD90+/Gran+ cell numbers. The data show that head-localized proton irradiation at relatively modest doses can profoundly influence systemic distribution and composition of lymphocyte populations. The data also suggest that immune modulation induced by localized proton, as well as other forms of radiation, should be taken into consideration when evaluating adjunctive immunotherapies in patients receiving radiotherapy.

Animals↗

PubMedDate not supplied

Whole-body irradiation and long-term modification of bone marrow-derived cell populations by low- and high-LET radiation.

BACKGROUND: The major aim of this study was to quantify long-term changes in bone marrow-derived cell populations after exposure to radiations of differing quality. MATERIALS AND METHODS: Mice were whole-body irradiated to 2 Gy gamma, proton, carbon or iron radiation, and euthanized approximately 110 days later for immunocyte phenotyping. RESULTS: Splenic lymphocytes and mono/macrophages increased after gamma-rays when compared to 0 Gy and one or more of the other groups. There were high T cells (carbon vs. 0 Gy), high B cells (gamma-rays vs. 0 Gy), and low natural killer (NK) cells (proton and carbon vs. 0 Gy). All radiations, except gamma-rays, increased CD62L+ memory T cell counts, whereas CD62L+ B cells increased only after gamma-rays. CONCLUSION: There were significant aberrations in many immune parameters nearly 4 months after exposure to various forms of radiation. This suggests radiation exposure can have long-term health consequences.

Animals↗