Kinetics of Neutrophils in Mice Exposed to Radiation and/or Granulocyte Colony-Stimulating Factor Treatment

Abstract

Astronauts have the potential to develop the hematopoietic syndrome as a result of exposure to radiation from a solar particle event (SPE) during exploration class missions. This syndrome is characterized by a reduction in the number of circulating blood cells (cytopenias). In the present study the effects of SPE-like proton and γ radiation on the kinetics of circulating neutrophils were evaluated during a one-month time period using mice as a model system. The results revealed that exposure to a 2 Gy dose of either SPE-like proton or γ radiation significantly decreased the number of circulating neutrophils, with two nadirs observed on day 4 and day 16 postirradiation. Low circulating neutrophil count (neutropenia) is particularly important because it can increase the risk of astronauts developing infections, which can compromise the success of the mission. Thus, two granulocyte colony-stimulating factors (G-CSFs), filgrastim and pegfilgrastim were evaluated as countermeasures for this endpoint. Both forms of G-CSF significantly increased neutrophil counts in irradiated mice, however, the effect of pegfilgrastim was more potent and lasted longer than filgrastim. Using the expression of CD11b, CD18 and the production of reactive oxygen species (ROS) as markers of neutrophil activation, it was determined that the neutrophils in the irradiated mice treated with pegfilgrastim were physiologically active. Thus, these results suggest that pegfilgrastim could be a potential countermeasure for the reduced number of circulating neutrophils in irradiated animals.

Biological effects of space radiation and development of effective countermeasures

“…Comparable results were observed in similar studies utilizing 74-MeV protons and 137 Cs γ-rays in which the changes in WBC counts were evaluated over time (145). The results from the studies in mice indicate that proton radiation is not more effective than the commonly used reference radiations with respect to effects on hematopoietic cells (135, 145). …”

“…The changes in peripheral leukocytes in animals post-irradiation have been evaluated in ICR mice irradiated with 225-kVp X-rays (132), γ-rays from 60 Co (133) or 137 Cs (134–136), protons with energies of 50-MeV (133), 51-MeV (137), 70-MeV (133), 74-MeV (134, 135), 78.4 MeV (138) and 1-GeV protons (137, 139) as well as protons with eight different energies between 31 and 75 MeV and simulated SPE protons with energies between 30 and 150 MeV (140). The changes in peripheral leukocytes have also been examined in ferrets irradiated with 60 Co or 137 Cs γ-rays and 110-MeV protons (141, 142) and Yucatan minipigs irradiated with 6-MeV electrons (130), 6+12-MeV electrons and SPE protons (143, 144).…”

“…To determine the RBE values for the effects of SPE protons in hematopoietic cells, several studies were performed in mice using 21-MeV electrons (150), 60 Co γ-rays (133) or 137 Cs γ-rays (135, 145) as the reference radiations. In male ICR mice irradiated with 2 Gy of 70-MeV protons or 21-MeV electrons, peripheral WBC, lymphocyte and granulocyte counts decreased significantly in the irradiated mice as compared to the sham irradiated control, but the differences between the proton and electron irradiated mice were not statistically significant for WBCs, lymphocytes or granulocytes (150).…”

“…In 5 to 6-week old female ICR mice irradiated with 60 Co γ-rays, 50-MeV protons or 70-MeV protons at low (0.5 Gy/hour) or high (0.5 Gy/minute) dose rate, the peripheral WBC count decreased in a dose-dependent manner at 24 hours post-irradiation and the RBE values for 50-MeV and 70-MeV protons at either low or high dose rate were not significantly different from 1 with 60 Co γ-rays as the reference radiation at the corresponding dose rates (133). In a separate study performed with 6-week old female ICR mice, the neutrophil count was monitored for 30 days post- irradiation with 0.5, 1 or 2 Gy of 137 Cs γ-rays or 74-MeV protons at dose rates of 0.44 Gy/minute and 0.5 Gy/minute, respectively (135). For the 2 Gy γ-ray and proton dose groups, the neutrophil counts decreased by approximately 65% and 70%, respectively, at the first nadir, which occurred on Day-4 post-irradiation, and then fully recovered by Day-10 post- irradiation to levels that were not significantly different from the pre-irradiation control level.…”

Involvement of IL-10 and granulocyte colony-stimulating factor in the fate of monocytes controlled by galectin-1

“…Recently, Romero-Weaver et al reported the ability of G-CSF to promote the proliferation of bone marrow stem cells and inhibit granulocyte apoptosis (12). G-CSF also improved the recovery from spinal cord injury in mice (13) and improved memory and neuro-behavior in an amyloid-β-induced experimental model of Alzheimer's disease (14).…”