Radiation research最新文献

Increased incidence of diabetes has been reported after whole-body irradiation in cancer survivors and in the years after exposure in research studies of nonhuman primates. Type 2 diabetes presents in the absence of obesity and suggests that skeletal muscle, the predominant organ responsible for minute-to-minute glucose disposal, is persistently dysfunctional. We evaluated skeletal muscle (SkM) from control (CTL, n = 8) and irradiated (IRRAD, n = 16) male rhesus macaques (Macaca mulatta) that had been exposed to an average whole-body dose of 6.5 Gy after an average of 4 years of follow-up. Irradiated animals had deficient SkM basal and insulin-stimulated receptor activation that was unrelated to histologically assessed fiber size, extracellular matrix and endothelial components. Protein extracted from irradiated muscle showed that Akt2, downstream of insulin receptor activation, was sulfenyl-modified and thus a target for radiation-related glycemic dysregulation. Shotgun proteomics identified upregulation of many mitochondrial and peroxisome-associated proteins, and increases were confirmed by immunoblotting of select protein targets. Proteomic pathway enrichment mapping showed distinct protein clustering between CTL and IRRAD groups. Mitochondrial proteins were surveyed and confirm that mitochondrial turnover may be increased after irradiation with higher fission and fusion markers. The results indicate that irradiated muscle is persistently insulin resistant, with evidence of intracellular protein oxidation and shifts in mitochondrial dynamics and function.

The Wake Forest Radiation Late Effects Cohort (RLEC), formerly known as the Radiation Survivors Cohort, of rhesus (Macaca mulatta) non-human primates (NHPs) is a unique colony of long-term survivors of total-body irradiation (TBI). The cohort includes 212 live animals, with 17% being unirradiated controls, and 104 deceased animals, including 15% controls. This cohort has been monitored for over 16 years, with an average observation period of 5 years. Irradiated NHPs were exposed to single TBI doses ranging from 1.14 to 8.5 Gy (average = 6.1 Gy). One animal received 10 Gy partial-body irradiation with approximately 5% bone marrow sparing. In this paper, we present the postmortem findings from 104 deceased members of the RLEC. Animals underwent a comprehensive, standardized necropsy, which included a complete gross and histopathologic examination of 36 organs and tissues. For this study, necropsy reports of 104 deceased animals (87 irradiated and 17 controls) were reviewed by two board-certified veterinary pathologists (GWS and JMC), and all diagnoses were cataloged. A total of 2,790 diagnoses were recorded across all organ systems and analyzed for statistical differences between irradiated and control animals using Fisher's exact test. Deceased control animals ranged in age from 9.9 to 21.4 years (mean = 16 years), whereas irradiated animals were younger, with ages from 2.7 to 23.1 years (mean = 11.6 years, P = 0.0001). The time from irradiation to death ranged from 0.3 to 14.4 years (average = 6.4 years). Radiation doses for these deceased animals ranged from 3.5 to 8.5 Gy (average = 6.6 Gy). The prevalence of most lesions was not statistically different from controls. Common findings among the irradiated animals included multi-organ fibrosis and chronic inflammation. Additionally, there was an increased occurrence of neoplasia in the irradiated animals. These data represent comprehensive, systemic, long-term pathology assessments conducted on a large group of NHPs years after total-body irradiation in the molecular era. They provide a solid foundation for molecular and translational studies of radiation late effects. The fact that many of the same lesions appeared in both the irradiated and unirradiated control animals, despite the significant age difference, suggests an accelerated-aging phenotype in the survivors.

Acute total-body irradiation (TBI) leads to transient dose-dependent lymphopenia. While lymphocyte numbers gradually recover, there remain subtle but long-lasting changes to B and T cell populations years after radiation exposure. The degree to which immunological memory is retained after TBI is unknown; however, it is conceivable that vaccine-induced protective immunity is jeopardized. To test this hypothesis, samples were collected from a cohort of rhesus macaques that were vaccinated against measles virus, irradiated, and then allowed to recover from the acute radiation effects for at least a year. Animals received 0 to 7.5 Gy TBI or 10 Gy with 5% bone marrow shielding. Plasma from 109 animals were evaluated for measles-binding antibodies and the ability to neutralize live measles virus. Females exhibited higher measles binding and neutralizing titers, and irradiated animals of both sexes exhibited significant radiation-dose dependent reductions in measles binding IgG and neutralizing titers. Peripheral blood mononuclear cells (PBMC) from the vaccinated, irradiated animals were then stimulated in vitro with measles antigens to evaluate cellular responses. No radiation-dose effects on CD8 T cell responses to measles antigens were detected. In contrast, PBMC from vaccinated, irradiated males exhibited radiation dose-dependent reductions in the percentages of CD4 T cells expressing activation-associated markers and cytokines in response to measles antigens. There were also significant dose- or dose/sex-interacting effects on the levels of IP10, MIP1β, and IL-6 present in the antigen-stimulated PBMC cultures. Cells from animals receiving 10 Gy with 5% bone marrow shielding exhibited signs of T-cell anergy. PBMC from females exhibited only weak responses to measles antigen stimulation regardless of radiation exposure. Collectively, these in vitro studies indicate that radiation can cause protracted dose- and sex-dependent damage to established humoral and cellular immunological memories of measles.

Wake Forest University School of Medicine (WFUSM) hosts the Radiation Late Effects Cohort (RLEC), a unique cohort of previously irradiated rhesus monkeys gathered from multiple institutions over twenty years. Supported by the National Institutes of Health's National Institute of Allergy and Infectious Diseases (NIH/NIAID) Radiation/Nuclear program, it serves as a resource for the Centers for Medical Countermeasures against Radiation Consortium (CMCRC) and the wider biomedical research community. These animals act as a national resource for examining the long-term effects of radiation exposure. Since its establishment in 2007, the RLEC has studied 328 macaques, including 270 exposed to external beam ionizing radiation and 58 controls. Results to date reveal a multisystemic pattern of chronic illness, including metabolic disease and diabetes mellitus, hypertension, higher rates of cancers, long-term immune impairment, myocardial disease, cerebrovascular disease, low body weight, gonadal injury with reduced sex steroid output, cataracts, osteopenia, renal disease, compromised intestinal barrier function, and ongoing systemic inflammation. This summary highlights the essential aspects of the RLEC, the significant achievements of researchers using this resource, and the potential for further investigation of this unique animal population and its associated resources.

Radiation-induced lung injury (RILI) includes early acute phase radiation pneumonitis (RP), and late chronic phase radiation-induced pulmonary fibrosis (RIPF). There is increasing evidence that ionizing radiation-induced cellular senescence is associated with pulmonary fibrosis. We have recently reported that biomarkers of senescence and, specifically, tyrosine kinase Fgr are induced in mouse RIPF, human idiopathic pulmonary fibrosis (IPF), and in human RIPF. We also reported that treatment with an Fgr inhibitor significantly reduced fibrosis of irradiated mouse lungs. Here, we investigated the association of senescence and tyrosine kinase Fgr in non-human primate (NHP) lung fibrosis and determined whether lung fibrosis can be predicted by analyzing the bronchoalveolar lavage (BAL) cells and fluid at early time points after irradiation. We found that markers of senescence (p16, p21) and expression of Fgr are induced in the lungs of NHP with RILI. That fibrosis can be predicted by analyzing BAL cells prior to the appearance of pulmonary fibrosis. We also induced senescence and expression of Fgr in irradiated normal human primary airway epithelial cells in vitro. In a transwell culture system, we established that senescent human airway epithelial cells induced fibrosis biomarkers collagen1, collagen 3, and alpha-smooth-muscle actin in target human primary lung fibroblasts. Whole-thorax lung irradiated (WTLI) NHPs in this study developed moderate to severe pneumonitis and marked variations in the magnitude of RIPF as measured by trichrome staining. In BAL fluid that was collected from WTLI NHP senescence-associated secretory proteins (SASP) were significantly induced, compared to the BAL fluid collected from control non-irradiated NHPs. Moreover, the levels of Fgr and biomarkers of senescence were significantly higher in NHPs with severely injured lungs compared to those with mildly or moderately injured lungs as indicated by fibrosis. Proinflammatory SASP cytokines increased to levels that correlated with the severity of RILI. The results show that senescent cells with induction of Fgr, and SASP cytokines are detectable in NHPs prior to RIPF and suggest that analysis of these proteins can predict the severity of RIPF prior to fully formed fibrosis.

The hematopoietic system is highly sensitive to ionizing radiation exposure. Accumulating evidence from the Japanese A-bomb survivor cohort and animal studies suggests that radiation-induced damage to the hematopoietic system can persist long after exposure, and therefore has the potential of contributing to delayed effects of acute radiation exposure (DEARE). In this study, archival data from the non-human primate radiation late effects cohort was analyzed to evaluate long-term effects on the hemopoietic system. The dataset included white blood cell and leukocyte differential counts from two hundred sixteen rhesus macaques (Macaca mulatta) exposed to 1.14 to 8.5 Gy and 47 non-irradiated control animals; blood samples were collected approximately 1-year post-acute uniform whole-body exposure and continuously thereafter every 2-6 months. Linear mixed models were developed for total leukocyte and differential counts, which included neutrophil, lymphocyte, and monocyte counts and percentages. Longitudinal trends were estimated for three dose ranges (low dose LD50/30, 6.8 to 8.5 Gy) and controls, and adjusted for sex and age at time of exposure. All models suggested that radiation dose was a statistically significant factor in the longitudinal trends of leukocyte and differential changes observed. Control and low-dose irradiated non-human primates (NHPs) presented a slight decrease in total leukocyte count and monocyte skewed differentiation, consistent with changes expected from natural aging of the hematopoietic system; longitudinal changes for the mid-dose LD50/30 NHPs than for the controls and

The Centers for Medical Countermeasures against Radiation Consortium (CMCRC) has provided a strong research foundation for the radiobiology science that will follow. After 20 years, however, the CMCRC will continue to conduct research on preparedness in niche areas of radiobiology and advanced product development, many of which were initiated by the CMCRC. This manuscript offers a review of past and current strategies and advancements in medical countermeasures to address radiation injuries, carried out by the CMCRC and funded by the National Institute of Allergy and Infectious Diseases Radiation and Nuclear Countermeasures Program. It also explores the mechanisms of radiation-induced injuries, discusses existing medical countermeasures, and highlights emerging technologies and potential future directions for radiobiology researchers. This review aims to enhance our understanding of current medical countermeasures against radiation and contribute to the future development of more efficient and innovative approaches to mitigate and treat radiation-induced damage.

Hair is an attractive sample for determining exposure to ionizing radiation due to its non-invasive nature. A biological tissue comprised mainly of keratin protein, hair is susceptible to oxidative or reductive stress by direct or indirect damage mechanisms. In this report, changes observed in the Raman spectra associated with hair protein from ionizing radiation were assessed for biodosimetry. Raman spectra were obtained from the hairs of a mixed sex cohort of irradiated C57BL/6 mice (N = 32 total) with doses of gamma rays ranging from 0-4 Gy. Radiation-dependent changes in the Raman spectra of the hairs provided molecular-specific signals that can inform about the damage mechanism. Partial least-squares discriminant analysis (PLS-DA) models incorporating automated variable selection for each sex showed classification of controls or exposed at 80% accuracy based on cross-validation. Models show only slight differences in performance based on the mouse's sex from which the sample originated. This slight difference is consistent with PLS-DA models that show marginal cross-validation sensitivity (∼60%) in predicting the sex of the mouse from the Raman hair spectrum. Utilizing PLS regression, a dose-response model including both sexes showed root-mean-squared error (RMSE) ±1 Gy. The ability to determine dose or exposure from plucked hair with Raman spectroscopy would provide a needed tool for rapid medical triage after unexpected exposure.

The rhesus macaque (Macaca mulatta) is the primary nonhuman primate (NHP) model used for the development of radiation medical countermeasures (MCMs), but due to the limited supply of rhesus macaques that has resulted from their need in other high priority medical research areas, alternative animal models for MCM development have been sought. The cynomolgus macaque (Macaca fascicularis) is less well characterized and less commonly used, but represents another quite viable, large animal NHP model for investigating MCMs. We have investigated the nature of injuries within selected organ systems induced by two potentially lethal doses (5.8 and 6.5 Gy) of ionizing radiation delivered as a total-body exposure to both rhesus and cynomolgus NHPs. Results suggest that the injuries within organs with strong self-renewing capacities (gastrointestinal and lymphohematopoietic systems) were comparable between the two NHP species, although the severity of the injuries differed. By contrast, the nature and seriousness of noted tissue pathologies were more comparable for other tissues with more limited self-renewal. In aggregate, however, the observed radiation-associated pathologies in various organs appeared to be more prominent within cynomolgus NHPs and hence, were somewhat more sensitive to the radiation exposures compared to rhesus NHPs.