RESUMO
Radiation dermatitis (RD) is one of the most common side effects of radiation therapy. However, to date, there is a lack of both specific treatments for RD and validated experimental animal models with the use of various sources of ionizing radiation (IR) applied in clinical practice. The aim of this study was to develop and validate a model of acute RD induced using proton radiation in mice. Acute RD (Grade 2-4) was obtained with doses of 30, 40, and 50 Gy, either with or without depilation. The developed model of RD was characterized by typical histological changes in the skin after irradiation. Moreover, the depilation contributed to a skin histology alteration of the irradiated mice. The assessment of animal vital signs indicated that there was no effect of proton irradiation on the well-being or general condition of the animals. This model can be used to develop effective therapeutic agents and study the pathogenesis of radiation-induced skin toxicity, including that caused by proton irradiation.
Assuntos
Síndrome Aguda da Radiação , Radiodermite , Animais , Camundongos , Prótons , Radiodermite/etiologia , Pele/efeitos da radiação , Síndrome Aguda da Radiação/complicações , Modelos TeóricosRESUMO
Thrombocytopenia is a major complication in hematopoietic-acute radiation syndrome (H-ARS) that increases the risk of mortality from uncontrolled hemorrhage. There is a great demand for new therapies to improve survival and mitigate bleeding in H-ARS. Thrombopoiesis requires interactions between megakaryocytes (MKs) and endothelial cells. 16, 16-dimethyl prostaglandin E2 (dmPGE2), a longer-acting analogue of PGE2, promotes hematopoietic recovery after total-body irradiation (TBI), and various angiotensin-converting enzyme (ACE) inhibitors mitigate endothelial injury after radiation exposure. Here, we tested a combination therapy of dmPGE2 and lisinopril to mitigate thrombocytopenia in murine models of H-ARS following TBI. After 7.75 Gy TBI, dmPGE2 and lisinopril each increased survival relative to vehicle controls. Importantly, combined dmPGE2 and lisinopril therapy enhanced survival greater than either individual agent. Studies performed after 4 Gy TBI revealed reduced numbers of marrow MKs and circulating platelets. In addition, sublethal TBI induced abnormalities both in MK maturation and in in vitro and in vivo platelet function. dmPGE2, alone and in combination with lisinopril, improved recovery of marrow MKs and peripheral platelets. Finally, sublethal TBI transiently reduced the number of marrow Lin-CD45-CD31+Sca-1- sinusoidal endothelial cells, while combined dmPGE2 and lisinopril treatment, but not single-agent treatment, accelerated their recovery. Taken together, these data support the concept that combined dmPGE2 and lisinopril therapy improves thrombocytopenia and survival by promoting recovery of the MK lineage, as well as the MK niche, in the setting of H-ARS.
Assuntos
16,16-Dimetilprostaglandina E2/uso terapêutico , Síndrome Aguda da Radiação/tratamento farmacológico , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Plaquetas/efeitos dos fármacos , Células Endoteliais/efeitos dos fármacos , Transtornos Hemorrágicos/tratamento farmacológico , Lisinopril/uso terapêutico , Megacariócitos/efeitos dos fármacos , Trombocitopenia/tratamento farmacológico , Trombopoese/efeitos dos fármacos , Síndrome Aguda da Radiação/complicações , Animais , Plaquetas/efeitos da radiação , Medula Óssea/efeitos dos fármacos , Medula Óssea/efeitos da radiação , Proteína C-Reativa/análise , Radioisótopos de Césio , Avaliação Pré-Clínica de Medicamentos , Células Endoteliais/efeitos da radiação , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/efeitos da radiação , Feminino , Raios gama/efeitos adversos , Transtornos Hemorrágicos/etiologia , Megacariócitos/efeitos da radiação , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/análise , Agregação Plaquetária/efeitos dos fármacos , Agregação Plaquetária/efeitos da radiação , Fator Plaquetário 4/análise , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/etiologia , Trombocitopenia/etiologia , Trombopoese/efeitos da radiação , Irradiação Corporal Total , Fator de von Willebrand/análiseRESUMO
The growing risk of accidental radiation exposure due to increased usage of ionizing radiation, such as in nuclear power, industries and medicine, has increased the necessity for the development of radiation countermeasures. Previously, we demonstrated the therapeutic potential of the acetylated diacylglycerol, 1-palmitoyl-2-linoleoyl-3-acetyl-rac-glycerol (PLAG), as a radiation countermeasure by mitigating radiation-associated mortality and hematopoietic acute radiation syndrome (H-ARS) in BALB/c mice after a lethal dose (LD70/30) of gamma-ray total-body irradiation (TBI). In this study, we show that PLAG mitigates symptoms of H-ARS, as characterized by mature blood cell recovery and restoration of bone marrow cellularity, by regulating systemic inflammation. Log-rank test demonstrated that high levels of WBCs, lymphocytes and neutrophils on day 10 post-TBI resulted in significantly improved survival rate. PLAG significantly enhanced the nadir values of all major blood cell types as well as bone marrow cellularity. A single TBI at LD70/30 induced an immediate increase in the blood levels of CXCL1 (12.5 fold), CXCL2 (1.5 fold), IL-6 (86.9 fold), C-reactive protein (CRP; 1.3 fold) and G-CSF (15.7 fold) at 6 h post-TBI, but the cytokine levels returned to baseline level afterward. When the irradiated mice started to die around 15 days post-TBI, they exhibited a second surge in blood levels of CXCL1 (49.3 fold), CXCL2 (87.1 fold), IL-6 (208 fold), CRP (3.6 fold) and G-CSF (265.7 fold). However, PLAG-treated groups showed a significant decrease in these same blood levels (P < 0.001). Considering the inverse correlation between inflammatory cytokine levels and hematological nadirs, PLAG exerts its therapeutic effects on H-ARS by regulating inflammatory cytokine production. These data suggest that PLAG has high potential as a radiation countermeasure to mitigate H-ARS after accidental exposure to radiation.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Diglicerídeos/uso terapêutico , Sistema Hematopoético/efeitos da radiação , Inflamação/tratamento farmacológico , Síndrome Aguda da Radiação/complicações , Animais , Modelos Animais de Doenças , Feminino , Inflamação/etiologia , Contagem de Leucócitos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Neutrófilos/citologia , Análise de Sobrevida , Irradiação Corporal TotalRESUMO
The nonhuman primate, rhesus macaque, is a relevant animal model that has been used to determine the efficacy of medical countermeasures to mitigate major signs of morbidity and mortality of radiation-induced lung injury. Herein, a literature review of published studies showing the evolution of lethal lung injury characteristic of the delayed effects of acute radiation exposure between the two significantly different exposure protocols, whole thorax lung irradiation and partial-body irradiation with bone marrow sparing in the nonhuman primate, is provided. The selection of published data was made from the open literature. The primary studies conducted at two research sites benefitted from the similarity of major variables; namely, both sites used rhesus macaques of approximate age and body weight and radiation exposure by LINAC-derived 6 MV photons at dose rates of 0.80 Gy min and 1.00 Gy min delivered to the midline tissue via bilateral, anterior/posterior, posterior/anterior geometry. An advantage relative to sex difference resulted from the use of male and female macaques by the Maryland and the Washington sites, respectively. Subject-based medical management was used for all macaques. The primary studies (6) provided adequate data to establish dose response relationships within 180 d for the radiation-induced lung injury consequent to whole thorax lung irradiation (male vs. female) and partial-body irradiation with bone marrow sparing exposure protocols (male). The dose response relationships established by probit analyses vs. linear dose relationships were characterized by two main parameters or dependent variables, a slope and LD50/180. Respective LD50/180 values for the primary studies that used whole thorax lung irradiation for respective male and female nonhuman primates were 10.24 Gy [9.87, 10.52] (n = 76, male) and 10.28 Gy [9.68, 10.92] (n = 40, female) at two different research sites. The respective slopes were steep at 1.73 [0.841, 2.604] and 1.15 [0.65, 1.65] probits per linear dose. The LD50/180 value and slope derived from the dose response relationships for the partial-body irradiation with bone marrow sparing exposure was 9.94 Gy [9.35, 10.29] (n = 87) and 1.21 [0.70, 1.73] probits per linear dose. A secondary study (1) provided data on limited control cohort of nonhuman primates exposed to whole thorax lung irradiation. The data supported the incidence of clinical, radiographic, and histological indices of the dose-dependent lung injury in the nonhuman primates. Tertiary studies (6) provided data derived from collaboration with the noted primary and secondary studies on control cohorts of nonhuman primates exposed to whole thorax lung irradiation and partial-body irradiation with bone marrow sparing exposure. These studies provided a summary of histological evidence of fibrosis, inflammation and reactive/proliferative changes in pneumonocytes characteristic of lung injury and data on biomarkers for radiation-induced lung injury based on matrix-assisted laser desorption ionization-mass spectrometry imaging and gene expression approaches. The available database in young rhesus macaques exposed to whole thorax lung irradiation or partial-body irradiation with bone marrow sparing using 6 MV LINAC-derived radiation with medical management showed that the dose response relationships were equivalent relative to the primary endpoint all-cause mortality. Additionally, the latency, incidence, severity, and progression of the clinical, radiographic, and histological indices of lung injury were comparable. However, the differences between the exposure protocols are remarkable relative to the demonstrated time course between the multiple organ injury of the acute radiation syndrome and that of the delayed effects of acute radiation exposure, respectively.
Assuntos
Síndrome Aguda da Radiação/complicações , Medula Óssea/patologia , Lesão Pulmonar/mortalidade , Tratamentos com Preservação do Órgão/métodos , Exposição à Radiação/efeitos adversos , Lesões Experimentais por Radiação/mortalidade , Tórax/patologia , Animais , Medula Óssea/efeitos da radiação , Comorbidade , Modelos Animais de Doenças , Lesão Pulmonar/etiologia , Lesão Pulmonar/patologia , Mortalidade/tendências , Primatas , Lesões Experimentais por Radiação/etiologia , Lesões Experimentais por Radiação/patologia , Tórax/efeitos da radiaçãoRESUMO
Murine hematopoietic-acute radiation syndrome (H-ARS) survivors of total body radiation (TBI) have a significant loss of heart vessel endothelial cells, along with increased tissue iron, as early as 4 mo post-TBI. The goal of the current study was to determine the possible role for excess tissue iron in the loss of coronary artery endothelial cells. Experiments used the H-ARS mouse model with gamma radiation exposure of 853 cGy (LD50/30) and time points from 1 to 12 wk post-TBI. Serum iron was elevated at 1 wk post-TBI, peaked at 2 wk post-TBI, and returned to non-irradiated control values by 4 wk post-TBI. A similar trend was seen for transferrin saturation, and both results correlated inversely with red blood cell number. Perls' Prussian Blue staining, used to detect iron deposition in heart tissue sections, showed myocardial iron was present as early as 2 wk following irradiation. Pretreatment of mice with the iron chelator deferiprone decreased tissue iron but not serum iron at 2 wk. Coronary artery endothelial cell density was significantly decreased as early as 2 wk vs. non-irradiated controls (P<0.05), and the reduced density persisted to 12 wk after irradiation. Deferiprone treatment of irradiated mice prevented the decrease in endothelial cell density at 2 and 4 wk post-TBI compared to irradiated, non-treated mice (P<0.03). Taken together, the results suggest excess tissue iron contributes to endothelial cell loss early following TBI and may be a significant event impacting the development of delayed effects of acute radiation exposure.
Assuntos
Síndrome Aguda da Radiação/complicações , Raios gama/efeitos adversos , Cardiopatias/etiologia , Sobrecarga de Ferro/complicações , Exposição à Radiação/efeitos adversos , Lesões Experimentais por Radiação/complicações , Animais , Feminino , Cardiopatias/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Doses de Radiação , Irradiação Corporal TotalRESUMO
The goal of this study is to understand and mitigate the effects of wounds on acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE), for preparedness against a radiological attack or accident. Combined injuries from concomitant trauma and radiation are likely in these scenarios. Either exacerbation or mitigation of radiation damage by wound trauma has been previously reported in preclinical studies. Female WAG/RijCmcr rats received 13 Gy X-rays, with partial-body shielding of one leg. Within 2 h, irradiated rats and non-irradiated controls were given full-thickness skin wounds with or without lisinopril, started orally 7 days after irradiation. Morbidity, skin wound area, breathing interval and blood urea nitrogen were measured up to 160 days post-irradiation to independently evaluate wound trauma and DEARE. Wounding exacerbated morbidity in irradiated rats between 5 and 14 days post-irradiation (during the ARS phase), and irradiation delayed wound healing. Wounding did not alter delayed morbidities from radiation pneumonitis or nephropathy after 30 days post-irradiation. Lisinopril did not mitigate wound healing, but markedly decreased morbidity during DEARE from 31 through 160 days. The results derived from this unique model of combined injuries suggest different molecular mechanisms of injury and healing of ARS and DEARE after radiation exposure.
Assuntos
Síndrome Aguda da Radiação/complicações , Lisinopril/farmacologia , Lesões Experimentais por Radiação , Pneumonite por Radiação/complicações , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/complicações , Animais , Nitrogênio da Ureia Sanguínea , Feminino , Estimativa de Kaplan-Meier , Lesões por Radiação , Proteção Radiológica , Ratos , Irradiação Corporal Total , Raios XRESUMO
BACKGROUND: Acute radiation enteritis (ARE), a common complication of intestinal caused by abdominal and pelvic radiation therapy. Rheinic acid is a major active ingredient derived from Rhubarb. Rhubarb could suppress inflammation, tumor, fibrosis oxidative damage. However, RA as the main active component and extract monomer of Rhubarb, the pharmacological activity and the underlying molecular mechanism on various diseases has not yet been revealed. OBJECTIVE: To determine the potential role of rheinic acid (RA) in ameliorating inflammation of rats with acute radiation enteritis (ARE), and explore the underlying mechanism. METHODS: ARE rat model was established by irradiated with single-dose 10 Gy X-rays at a rate of 0.62 Gy/min to the abdomen. The rats were executed after orally administered with Rheinic acid 7 days and used in the subsequent experiments. Body weight, fecal characteristics and bloody of rats were used to assess the disease activity index. Histological analysis of the jejunum and colon were evaluated using H&E staining. The pro-inflammatory cytokines levels were measured by immunohistochemistry and ELISA. The levels of nitric oxide (NO), malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) were also determined. The mRNA and protein expression were examined by real-time polymerase chain reaction (qRT-PCR) and western blot, respectively. RESULTS: Rheinic acid promoted intestinal functional recovery, and ameliorated intestinal damage and bloody stool in ARE rats. Rheinic acid strongly decreased the levels of tumor necrosis factor-α, interleukin-1, interleukin-6, NO, and MDA, whereas increased levels of anti-oxidants, SOD and GSH. Moreover, the expression of apoptosis-related proteins, cleaved caspase-3 and cleaved poly (ADP-ribose) polymerase (PARP), were decreased with RA treatment. Further study indicated that PPAR-γ was activated and thereby NF-κB and p38 MAPK signaling pathway were suppressed after rheinic acid treatment. CONCLUSION: Rheinic acid could ameliorate acute radiation enteritis and the underlying molecular mechanism is, at least partially, through PPAR-γ/NF-κB and p38 MAPK/JNK pathways.
Assuntos
Síndrome Aguda da Radiação/tratamento farmacológico , Antraquinonas/uso terapêutico , Enterite/tratamento farmacológico , NF-kappa B/metabolismo , PPAR gama/metabolismo , Protetores contra Radiação/uso terapêutico , Síndrome Aguda da Radiação/complicações , Animais , Antraquinonas/farmacologia , Apoptose , Colo/efeitos dos fármacos , Colo/metabolismo , Colo/efeitos da radiação , Citocinas/metabolismo , Enterite/etiologia , Glutationa/metabolismo , Jejuno/efeitos dos fármacos , Jejuno/metabolismo , Jejuno/efeitos da radiação , Masculino , Malondialdeído/metabolismo , Óxido Nítrico/metabolismo , Protetores contra Radiação/farmacologia , Ratos , Ratos Sprague-Dawley , Superóxido Dismutase/metabolismoRESUMO
A high-casualty incident may result in a significant human toll due to the inability of a community to meet the health care demands of the population. A successful medical response requires health care facilities to not only communicate and integrate medical services, meet surge capacity, protect health care workers and implement triage and treatment protocols, but also to provide the venue for clinical management of acute radiation injuries and their associated infections. Today, clinical management is primarily guided by the recommendations of a Consultancy that were made at the World Health Organization (WHO). This international consensus was reached on evidence-based, clinical management of each of the four sub-syndromes that compose acute radiation syndrome (ARS), including the hematopoietic subsyndrome (HS), gastrointestinal subsyndrome (GIS), neurovascular subsyndrome (NVS) and cutaneous subsyndrome (CS). Major findings in studies meeting inclusion criteria for management strategies for HS were that (i) no randomized controlled studies of medical countermeasures have been (or will likely ever be) performed for ARS cases, (ii) the data for management of HS are restricted by the lack of comparator groups, and (iii) reports of countermeasures for management of injury to non-hematopoietic organs are often incompletely described. Here, (i) recommendations made in Geneva are summarized; (ii) the analysis of countermeasures for HS is updated by review of two additional cases and extended to published reports not meeting inclusion criteria; and (iii) guidelines are provided for management of microbial infections based upon patient risk for prolonged immunosuppression.
Assuntos
Síndrome Aguda da Radiação/complicações , Síndrome Aguda da Radiação/terapia , Doenças Transmissíveis/terapia , Incidentes com Feridos em Massa , Antibacterianos/uso terapêutico , Doenças Transmissíveis/tratamento farmacológico , Humanos , Guias de Prática Clínica como Assunto , Organização Mundial da SaúdeRESUMO
Animal models of hematopoietic and gastrointestinal acute radiation syndromes (ARS) have been characterized to develop medical countermeasures. Acute radiation-induced decrease of intestinal absorptive function has been correlated to a decrease in the number of intestinal crypt cells resulting from apoptosis and enterocyte mass reduction. Citrulline, a noncoded amino acid, is produced almost exclusively by the enterocytes of the small intestine. Citrullinemia has been identified as a simple, sensitive and suitable biomarker for radiation-induced injury associated with gastrointestinal ARS (GI-ARS). Here we discuss the effect of radiation on plasma citrulline levels in three different species, C57BL/6 mice, Göttingen minipigs and rhesus nonhuman primates (NHPs), measured by liquid chromatography tandem mass spectrometry (LC-MS/MS). The effects of experimental study conditions such as feeding and anesthesia were also examined on plasma citrulline levels in the NHPs. Both the mice and Göttingen minipigs were partial-body irradiated (PBI) with doses from 13-17 Gy and 8-16 Gy, respectively, whereas NHPs were total-body irradiated (TBI) with doses from 6.72-13 Gy. Blood samples were taken at different time points and plasma citrulline levels were measured in the three species at baseline and after irradiation. Basal plasma citrulline concentrations (mean ± SEM) in mice and minipigs were 57.8 ± 2.8 µM and 63.1 ± 2.1 µM, respectively. NHPs showed a basal plasma citrulline concentration of 32.6 ± 0.7 µM, very similar to that of humans (â¼40 µM). Plasma citrulline progressively decreased after irradiation, reaching nadir values between day 3.5 and 7. The onset of citrulline recovery was observed earlier at lower radiation doses, while only partial citrulline recovery was noted at higher radiation doses in minipigs and NHPs, complete recovery was noted in mice at all doses. Plasma citrulline levels in NHPs anesthetized with ketamine and acepromazine significantly decreased by 35.5% (P = 0.0017), compared to unanesthetized NHPs. In the postprandial state, citrulline concentrations in NHPs were slightly but significantly decreased by 12.2% (P = 0.0287). These results suggest that plasma citrulline is affected by experimental conditions such as anesthesia and feeding.
Assuntos
Síndrome Aguda da Radiação/sangue , Citrulina/sangue , Gastroenteropatias/sangue , Acepromazina/farmacologia , Síndrome Aguda da Radiação/complicações , Animais , Biomarcadores/sangue , Citrulinemia/complicações , Ingestão de Alimentos , Gastroenteropatias/complicações , Ketamina/farmacologia , Camundongos , Especificidade da Espécie , Suínos , Porco MiniaturaRESUMO
Use of the tacticts of multistage surgical treatment on the model of combined radiation-and-mechanic injury. The article provides information on the use of the tactics of multistage surgical treatment (MST), which allows increasing survival value in patients with polytrauma. There are no descriptions of possibility of the use of this tactics in case of combined radiation-and-mechanic injuries in available literature. During an experimental research underwent on 25 sheep it was found that in case of MST implementation there is a significant decrease of intraoperative and postoperative lethal outcome in comparison with traditional tactics. In animals, underwent MST, were defined more laudable course of radiation syndrome. Analysis of laboratory peripheral blood indexes allowed making conclusion, that conducting final surgical intervention (3'd stage of MST) during the first 24 hours after abbreviated surgical intervention allows finishing surgical treatment and intensive care before the beginning of acute radiation syndrome and doesn't counter classic recommendations concerning the treatment of combined radiation-and-mechanic injuries.
Assuntos
Síndrome Aguda da Radiação , Medicina Militar/métodos , Procedimentos Cirúrgicos Operatórios/métodos , Lesões Relacionadas à Guerra , Síndrome Aguda da Radiação/complicações , Síndrome Aguda da Radiação/cirurgia , Animais , Modelos Animais de Doenças , Feminino , Humanos , Masculino , Ovinos , Lesões Relacionadas à Guerra/complicações , Lesões Relacionadas à Guerra/cirurgiaRESUMO
It is shown, that tactics of treatment of acute marrow failure of radiant etiology is based, first of all, on measures of supporting, replaceable and stimulating therapy. The modern means, used for prophylactic and treatment of infectious complications, are resulted. Opportunities and restrictions of transfusion of donor thrombocytes and granulocytes, erythrocytes and chilled plasma are described. Therapeutic efficiency of transplantation of a bone marrow, cells of embryonic liver and stem cells of peripheral or umbilical cord blood is analyzed. It is shown, that the greatest prospects in perfection of the specialized medical aid at acute radiation syndrome are connected to complex application of interleukin-1beta, interleukin-3, granulocyte or granulocyte/macrophage colony stimulated factor, thrombopoietin and others cytokines.
Assuntos
Síndrome Aguda da Radiação/terapia , Atenção à Saúde , Hemoglobinúria Paroxística/terapia , Síndrome Aguda da Radiação/complicações , Anemia Aplástica , Doenças da Medula Óssea , Transtornos da Insuficiência da Medula Óssea , Transplante de Medula Óssea , Controle de Doenças Transmissíveis/métodos , Doenças Transmissíveis/etiologia , Citocinas/administração & dosagem , Citocinas/uso terapêutico , Atenção à Saúde/organização & administração , Atenção à Saúde/normas , Atenção à Saúde/tendências , Hemoglobinúria Paroxística/complicações , Humanos , Guias de Prática Clínica como Assunto , Transplante de Células-Tronco , Transplante AutólogoRESUMO
Our earlier results demonstrated that clinically relevant concentrations of unconjugated bilirubin (UCB) possessed immunotoxic effects. Whole-body irradiation (WBI) with 1 to 6 Gy leads to acute radiation syndrome, immunosuppression, and makes the host susceptible to infection. Since hyperbilirubinemia has been shown to be associated with several types of cancer, the present studies were undertaken to evaluate the radiomodifying effects of UCB in radiation-exposed mice having elevated levels of UCB. Pretreatment of splenic lymphocytes with UCB (1-50 µM at UCB/BSA ratio <1) augmented radiation-induced DNA strand breaks, MMP loss, calcium release, and apoptosis. Combination treatment of mice with UCB (50mg/kg bw) followed by WBI (2 Gy) 0.5h later, resulted in significantly increased splenic atrophy, bone marrow aplasia, decreased counts of peritoneal exudate cells, and different splenocyte subsets such as CD3+ T, CD4+ T, CD8+ T, CD19+ B, and CD14+ macrophages as compared to either UCB or WBI treatment. Hematological studies showed that WBI-induced lymphopenia, thrombocytopenia, and neutropenia were further aggravated in the combination treatment group. UCB pretreatment of mice potentiated WBI-induced apoptosis and decreased WBI-induced loss of functional response of various immune cells leading to augmentation of immunosuppression and infection susceptibility caused by WBI. In an acute bacterial peritonitis model, UCB pretreatment of mice significantly increased WBI-induced proinflammatory cytokines, nitric oxide, and peritoneal bacterial load resulting in increased infection and death. Studies using the pharmacological inhibitor of p38MAPK demonstrated the involvement of p38MAPK activation in the inflammatory cascade of peritonitis. These findings should prove useful in understanding the potential risk to hyperbilirubinemic patients during radiotherapy and victims of acute radiation exposure in the course of radiation accidents.
Assuntos
Síndrome Aguda da Radiação/induzido quimicamente , Síndrome Aguda da Radiação/complicações , Bilirrubina/toxicidade , Infecções/complicações , Síndrome Aguda da Radiação/etiologia , Animais , Apoptose/efeitos dos fármacos , Cálcio/metabolismo , Citocinas/metabolismo , Dano ao DNA , Relação Dose-Resposta a Droga , Relação Dose-Resposta à Radiação , Infecções/induzido quimicamente , Linfócitos/efeitos dos fármacos , Macrófagos/efeitos dos fármacos , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Óxido Nítrico/metabolismo , Estresse Oxidativo/efeitos dos fármacos , Baço/citologia , Baço/efeitos dos fármacos , Irradiação Corporal Total , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
Due to the ever-present threat of a radiological or nuclear accident or attack, the National Institute of Allergy and Infectious Diseases, Radiation Medical Countermeasures Program was initiated in 2004. Since that time, the Program has funded research to establish small and large animal models for radiation damage, as well as the development of approaches to mitigate/treat normal tissue damage following radiation exposure. Because some of these exposures may be high-dose, and yet heterogeneous, the expectation is that some victims will survive initial acute radiation syndromes (e.g. hematopoietic and gastrointestinal), but then suffer from potentially lethal lung complications. For this reason, efforts have concentrated on the development of animal models of lung irradiation damage that mimic expected exposure scenarios, as well as drugs to treat radiation-induced late lung sequelae including pneumonitis and fibrosis. Approaches targeting several pathways are under study, with the eventual goal of licensure by the United States Food and Drug Administration for government stockpiling. This Commentary outlines the status of countermeasure development in this area and provides information on the specifics of licensure requirements, as well as guidance and a discussion of challenges involved in developing and licensing drugs and treatments specific to a radiation lung damage indication.
Assuntos
Pneumopatias/prevenção & controle , Pulmão/efeitos da radiação , Guerra Nuclear , Protetores contra Radiação/uso terapêutico , Liberação Nociva de Radioativos , Síndrome Aguda da Radiação/complicações , Síndrome Aguda da Radiação/tratamento farmacológico , Experimentação Animal/legislação & jurisprudência , Animais , Biomarcadores , Humanos , Licenciamento , Pneumopatias/tratamento farmacológico , Pneumopatias/etiologia , Modelos Animais , National Institute of Allergy and Infectious Diseases (U.S.) , Fibrose Pulmonar/etiologia , Fibrose Pulmonar/prevenção & controle , Lesões Experimentais por Radiação/tratamento farmacológico , Lesões Experimentais por Radiação/prevenção & controle , Pneumonite por Radiação/tratamento farmacológico , Pneumonite por Radiação/prevenção & controle , Tolerância a Radiação , Protetores contra Radiação/provisão & distribuição , Cinza Radioativa/efeitos adversos , Estados Unidos , United States Food and Drug AdministrationRESUMO
The 1986 Chernobyl Nuclear Power Plant accident that occurred is known as the most severe nuclear disaster in the history of humankind. Acute radiation syndrome (ARS) was diagnosed in 237 persons but only 134 of those were confirmed, including 28 patients who died due to lethal total-body gamma-irradiation and severe skin injuries caused by beta/gamma-emitting radionuclides. A small group of ARS survivors offers an interesting observational insight pertinent to the on-going discussions about long-term non-cancer effects of ionizing radiation. This descriptive study summarizes more than 20 y of follow-up, makes attempts to offer a prognosis for the Chernobyl ARS survivors' health, and explores the link between the outcomes of interest and radiation exposure.