Indiana University-Purdue University Indianapolis (IUPUI) / There is an urgent demand for effective medical countermeasures (MCM) in the event of high-dose radiation exposure ranging from nuclear plant disasters to potential nuclear warfare. Victims of lethal-dose radiation exposure face multi-organ injuries including the hematopoietic acute radiation syndrome (H-ARS) and the delayed effects of acute radiation exposure (DEARE) years after irradiation. Defective lymphocyte reconstitution and its subsequent immune insufficiency are some of the most serious consequences of H-ARS and DEARE. In order to investigate potential MCMs to protect or mitigate these radiation injuries, the prolonged tissue-specific immunosuppression at all levels of lymphocyte development in established murine H-ARS and DEARE models was defined, along with unique sex-related and age-related changes present in some tissues but not others. The “double hits” of irradiation and age-related stress on lymphopoiesis led to significant myeloid skew and long-term immune involution. Different kinds and different combinations of hematopoietic growth factors, some in combination with angiotensin converting enzyme inhibitor, were administered to lethally irradiated mice. These radiomitigators were found to significantly increase survival and enhance hematopoiesis in H-ARS, but they did little to alleviate the severity of DEARE including immune insufficiency. 16,16 dimethyl-prostaglandin E2 (dmPGE2), a long-acting formulation of PGE2 with similar biological effects as PGE2, was found to enhance survival and hematopoiesis in lethal-irradiated mice when used as radiomitigator or radioprotectant. The optimum time window for administration of radioprotectant and radiomitigator dmPGE2 was defined, which is -3hr to -15min prior to irradiation and +6hr to +30hr post irradiation. Significant survival efficacy of radioprotectant dmPGE2 was also demonstrated in pediatric and geriatric mice. Using specific PGE2 receptor (EP) agonists, the EP4 receptor was defined as the PGE2 receptor potentially responsible for dmPGE2 radioprotection. Radioprotectant dmPGE2 was also found to prevent radiation-induced thymic involution and to ameliorate the long-term immune suppression in radiation survivors in the DEARE phase via promoting hematopoietic stem cell differentiation towards to the lymphoid lineage. This is the first report of an effective MCM for H-ARS which also targets long-term thymic involution and lymphoid lineage reconstitution.

Exposure to radiation has toxic effects and for this reason research on food or drugs with positive radiomodifying action (protective) is of outmost interest to Public Health and Consumer Protection. Thus, the aim of this study was testing the prospect grape juice (Vitis labrusca) as a positive radiomodifier of biological effects that characterize the Acute Radiation Syndrome (ARS). Sixteen male Wistar rats divided into four groups were used, where two groups are acutelly whole body X-irradiated and two were sham X-irradiated with a 200 kV X-rays machine specially designed for biological samples at the University of Leon, Spain. The rats received 10 ml of grape juice or placebo (isocaloric solution of glucose and fructose) to be consumed ad libitum one week before and two weeks after 6 Gy Xirradiation, when they were euthanasiated. Physiopathological, biomolecular and biochemical indications of ARS (anorexia, body weight and major organs, hematological parameters, and indicators of oxidative metabolism) were evaluated and compared with respect to the gastrointestinal system (liver). Results were in agreement with our hypotesis about a potential positive radiomodifier effect of grape juice intake against ARS. / A exposição à radiação ionizante possui efeitos tóxicos indesejáveis e por este motivo investigações sobre alimentos ou fármacos com ação radiomodificadora positiva (protetora) é de grande interesse para a Saúde e Defesa Pública Nacional. Neste sentido, esta tese tem como perspectiva testar o suco de uva organicamente produzido (Vitis labrusca) como um radiomodificador positivo dos efeitos biológicos que caracterizam a Síndrome Aguda da Radiação (SAR). Para tanto foram utilizados 16 ratos Wistar machos divididos em quatro grupos, onde dois grupos foram irradiados de corpo inteiro de forma aguda com raios-X utilizando um irradiador de 200 kV especialmente concebido para amostras biológicas instalado na Universidad de León, Espanha. Os ratos receberam diariamente 10 ml de suco de uva ou placebo (solução isocalórica de glicose e frutose) para serem ingeridos ad libitum uma semana antes e duas depois da irradiação com 6 Gy de dose absorvida, quando foram eutanasiados. Foram avaliados e comparados parâmetros morfológicos, fisiológicos, biomoleculares e bioquímicos indicativos da SAR (anorexia, peso corporal e dos principais órgãos, parâmetros hematológicos, e indicadores do metabolismo oxidativo) no sistema gastrointestinal (fígado). Os resultados corroboram a hipótese de que a ingestão ad libitum crônica do suco de uva exerce efeito radiomodificador positivo contra a SAR.