RESUMO
BACKGROUND: Exogenous replacement of depleted enterocyte intestinal alkaline phosphatase (IAP) decreases intestinal injury in models of colitis. We determined whether radiation-induced intestinal injury could be mitigated by oral IAP supplementation and the impact on tissue-nonspecific AP. METHODS: WAG/RjjCmcr rats (n = 5 per group) received lower hemibody irradiation (13 Gy) followed by daily gavage with phosphate-buffered saline or IAP (40 U/kg/d) for 4 days. Real-time polymerase chain reaction, AP activity, and microbiota analysis were performed on intestine. Lipopolysaccharide and cytokine analysis was performed on serum. Data were expressed as a mean ± SEM with P greater than .05 considered significant. RESULTS: Intestine of irradiated animals demonstrates lower hemibody irradiation and is associated with upregulation of tissue-nonspecific AP, downregulation of IAP, decreased AP activity, and altered composition of the intestinal microbiome. CONCLUSIONS: Supplemental IAP after radiation may be beneficial in mitigating intestinal radiation syndrome as evidenced by improved histologic injury, decreased acute intestinal inflammation, and normalization of intestinal microbiome.
Assuntos
Fosfatase Alcalina/administração & dosagem , Fosfatase Alcalina/metabolismo , Microbioma Gastrointestinal , Intestinos/enzimologia , Radioterapia/efeitos adversos , Animais , Citocinas/metabolismo , Regulação para Baixo , Avaliação Pré-Clínica de Medicamentos , Íleo/enzimologia , Intestinos/efeitos da radiação , Lipopolissacarídeos/metabolismo , Masculino , Óxido Nítrico Sintase/genética , Óxido Nítrico Sintase/metabolismo , RNA Mensageiro/metabolismo , Dosagem Radioterapêutica , Ratos , Reação em Cadeia da Polimerase em Tempo Real , Regulação para CimaRESUMO
Our long-term goal is to use angiotensin converting enzyme (ACE) inhibitors to mitigate the increase in lung collagen synthesis that is induced by irradiation to the lung, which could result from accidental exposure or radiological terrorism. Rats (WAG/RijCmcr) were given a single dose of 13 Gy (dose rate of 1.43 Gy/min) of X-irradiation to the thorax. Three structurally-different ACE inhibitors, captopril, enalapril and fosinopril were provided in drinking water beginning 1 week after irradiation. Rats that survived acute pneumonitis (at 6-12 weeks) were evaluated monthly for synthesis of lung collagen. Other endpoints included breathing rate, wet to dry lung weight ratio, and analysis of lung structure. Treatment with captopril (145-207 mg/m(2)/day) or enalapril (19-28 mg/m(2)/day), but not fosinopril (19-28 mg/m(2)/day), decreased morbidity from acute pneumonitis. Lung collagen in the surviving irradiated rats was increased over that of controls by 7 months after irradiation. This increase in collagen synthesis was not observed in rats treated with any of the three ACE inhibitors. Analysis of the lung morphology at 7 months supports the efficacy of ACE inhibitors against radiation-induced fibrosis. The effectiveness of fosinopril against fibrosis, but not against acute pneumonitis, suggests that pulmonary fibrosis may not be a simple consequence of injury during acute pneumonitis. In summary, three structurally-different ACE inhibitors mitigate the increase in collagen synthesis 7 months following irradiation of the whole thorax and do so, even when therapy is started one week after irradiation.
Assuntos
Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Captopril/uso terapêutico , Colágeno/biossíntese , Enalapril/uso terapêutico , Fosinopril/uso terapêutico , Regulação da Expressão Gênica/efeitos da radiação , Fibrose Pulmonar/prevenção & controle , Pneumonite por Radiação/tratamento farmacológico , Tórax/efeitos da radiação , Inibidores da Enzima Conversora de Angiotensina/farmacologia , Animais , Captopril/farmacologia , Relação Dose-Resposta à Radiação , Avaliação Pré-Clínica de Medicamentos , Enalapril/farmacologia , Feminino , Fibrose , Fosinopril/farmacologia , Pulmão/efeitos dos fármacos , Pulmão/metabolismo , Pulmão/patologia , Pulmão/efeitos da radiação , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia , Pneumonite por Radiação/complicações , Pneumonite por Radiação/metabolismo , Pneumonite por Radiação/patologia , Ratos , Sistema Renina-Angiotensina/fisiologiaRESUMO
We recently reported that daily dietary supplementation with 100 µg selenium (a dose exceeding a rat's nutritional requirement by about 33-fold) initiated immediately after total-body irradiation (TBI) and maintained for 21 weeks mitigates radiation nephropathy in a rat model as indicated by blood urea nitrogen (BUN) levels and histopathological criteria (Radiat Res. 2009; 17:368-73). In this follow-up study, we explored the risks and benefits of delaying the onset of supplementation, shortening periods of supplementation, and escalating selenium supplementation beyond 100 µg/day. Supplementation with 200 µg selenium/day (as selenite or seleno-l-methionine) substantially improved the mitigation of radiation nephropathy by lowering BUN levels at 4 months after TBI from 115 to as low as 34 mg/dl and by proportionally lowering the incidence of histopathological abnormalities. Shortening the period of supplementation to 3 or 2 months did not compromise efficacy. Delaying the onset of supplementation for 1 week reduced but did not abrogate the mitigation of radiation nephropathy. Supplementation with 300 µg/day mitigated radiation nephropathy less effectively than 200 µg and was poorly tolerated. Rats that had been given 10 Gy of TBI were less tolerant of high-dose selenium than nonirradiated rats. This reduced tolerance of high-dose selenium would need to be taken into consideration when selenium is used for the mitigation of radiation injury in victims of nuclear accidents or acts of radiological terrorism. The high dose requirements, the pronounced threshold effect, and the superior performance of selenite suggest that the mitigation of radiation nephropathy involves mechanisms that go beyond the induction of selenoproteins.
Assuntos
Dieta , Lesões por Radiação/prevenção & controle , Selênio/administração & dosagem , Animais , Relação Dose-Resposta a Droga , Esquema de Medicação , Humanos , RatosRESUMO
PURPOSE: To find the mitigators of pneumonitis induced by moderate doses of thoracic radiation (10-15 Gy). METHODS AND MATERIALS: Unanesthetized WAG/RijCmcr female rats received a single dose of X-irradiation (10, 12, or 15 Gy at 1.615 Gy/min) to the thorax. Captopril (an angiotensin-converting enzyme inhibitor) or losartan (an angiotensin receptor blocker) was administered in the drinking water after irradiation. Pulmonary structure and function were assessed after 8 weeks in randomly selected rats by evaluating the breathing rate, ex vivo vascular reactivity, and histopathologic findings. Survival analysis was undertaken on all animals, except those scheduled for death. RESULTS: Survival after a dose of 10 Gy to the thorax was not different from that of unirradiated rats for Assuntos
Antagonistas de Receptores de Angiotensina
, Inibidores da Enzima Conversora de Angiotensina/uso terapêutico
, Captopril/uso terapêutico
, Losartan/uso terapêutico
, Pneumonite por Radiação/tratamento farmacológico
, Sistema Renina-Angiotensina/efeitos dos fármacos
, Inibidores da Enzima Conversora de Angiotensina/administração & dosagem
, Animais
, Captopril/administração & dosagem
, Avaliação Pré-Clínica de Medicamentos/métodos
, Feminino
, Losartan/administração & dosagem
, Pulmão/patologia
, Pulmão/fisiopatologia
, Pulmão/efeitos da radiação
, Artéria Pulmonar/efeitos dos fármacos
, Artéria Pulmonar/fisiologia
, Artéria Pulmonar/efeitos da radiação
, Doses de Radiação
, Lesões Experimentais por Radiação/tratamento farmacológico
, Lesões Experimentais por Radiação/mortalidade
, Lesões Experimentais por Radiação/patologia
, Lesões Experimentais por Radiação/fisiopatologia
, Pneumonite por Radiação/mortalidade
, Pneumonite por Radiação/patologia
, Pneumonite por Radiação/fisiopatologia
, Ratos
, Sistema Renina-Angiotensina/fisiologia
, Mecânica Respiratória/efeitos dos fármacos
, Mecânica Respiratória/fisiologia
, Mecânica Respiratória/efeitos da radiação
, Fatores de Tempo
, Vasoconstrição/efeitos dos fármacos
, Vasoconstrição/fisiologia
, Vasoconstrição/efeitos da radiação
, Vasodilatação/efeitos dos fármacos
, Vasodilatação/fisiologia
, Vasodilatação/efeitos da radiação
RESUMO
The purpose of this study was to evaluate in an animal model the safety and efficacy of dietary supplementation with high doses of selenium for the mitigation of the type of radiation injury that might be sustained during a nuclear accident or an act of radiological terrorism. Age-matched male rats were exposed to 10 Gy (single dose) of total-body irradiation (TBI) followed by a syngeneic bone marrow transplant, then randomized to standard drinking water or drinking water supplemented with sodium selenite or seleno-l-methionine. At 21 weeks after TBI, most rats on standard drinking water had severe renal failure with a mean blood urea nitrogen (BUN) level of 124 +/- 29 mg/dl (geometric mean +/- SE) whereas rats on selenium-supplemented drinking water (100 microg/day) had a mean BUN level of 67 +/- 12 mg/dl. The mitigating effect of selenium was confirmed by histopathological analyses. None of the animals on high-dose selenium showed signs of selenium toxicity. Our results suggest that dietary supplementation with high-dose selenium may provide a safe, effective and practical way to mitigate radiation injury to kidneys.