Renal dysfunction after total body irradiation: dose-effect relationship: in regard to Kal and van Kempen-Harteveld (Int J Radiat Oncol Biol Phys 2006;65:1228-1232).
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Humans↗
Biomedical subjects
John E Moulder
Publications and source records attributed to John E Moulder.
Arachidonic acid metabolites mediate the radiation-induced increase in glomerular albumin permeability.
Radiation-induced renal injury is characterized by proteinuria, hypertension, and progressive decline in renal function. We have previously shown that in vivo or in vitro irradiation of glomeruli with a single dose of radiation (9.5 Gy) increases glomerular albumin permeability (P(alb)) within 1 hr. The current studies tested the hypothesis that this early radiation-induced increase in P(alb) is caused by the release of arachidonic acid and by the generation of specific arachidonic acid metabolites. Glomeruli obtained from WAG/Rij/MCW rats and cultured rat glomerular epithelial and mesangial cells were studied after irradiation (9.5 Gy, single dose). Arachidonic acid release and eicosanoid synthesis by glomeruli or cultured glomerular cells were measured after irradiation, and the effect of inhibitors of phospholipase A2 (PLA2) and cyclooxygenase (COX) on the irradiation-induced increase in P(alb) was assessed. Arachidonic acid release was demonstrated within 10 mins of irradiation of isolated glomeruli and monolayer cultures of glomerular epithelial and mesangial cells. Prostaglandin F(2alpha) (PGF(2alpha)) and PGE2 release was increased after irradiation of isolated glomeruli. Blocking arachidonic acid release or COX activity before irradiation completely prevented the increase in P(alb). COX inhibition immediately after irradiation also diminished the radiation-induced increase in P(alb). We conclude that arachidonic acid and its COX metabolites play an essential role in the early cellular changes that lead to the radiation-induced increase in P(alb). Understanding of the early epigenetic effects of irradiation may lead to new intervention strategies against radiation-induced injury of normal tissues.
Albumins↗
Publishing negative results: the problem of publication bias.
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Bias↗
Potential deployment of angiotensin I converting enzyme inhibitors and of angiotensin II type 1 and type 2 receptor blockers in cancer chemotherapy.
There is significant evidence that both angiotensin I converting enzyme inhibitors (ACEI) and type 1 and type 2 angiotensin 2 (A2) receptor blockers may inhibit tumor growth. The finding is supported by many reports where these two classes of drugs showed cytostatic effects on the cultures of several lines of both normal and neoplastic cells. These drugs often transformed the cellular biochemical structures, especially in neoplastic cell lines. The same drugs also delayed the growth of different types of tumors in a variety of experimental animals (breast and lung carcinoma in mice; sarcomas, squamous cell carcinomas and hepatocellular carcinomas in rats), and there are a few reports of successful treatment of a limited number of cases of Kaposi sarcoma and gliomas with these drugs. Retrospective studies in hypertensive subjects treated with ACEI or A2 receptor blockers also seem to indicate that the incidence and growth of different neoplasms was delayed when these patients were compared to hypertensive patients receiving alternate medications. There is strong indication that the pharmacologic effect of these drugs may be exerted by reduction or inhibition of the synthesis of angiotensin 2. A2 is a powerful mitogen and its effect on cellular growth is exerted through stimulation of many factors, including transforming growth factor beta (TGFbeta), epidermal growth factor (EGF), smooth muscle actin (SMA), and tyrosine kinase. A2 also regulates apoptotic mechanisms and angiogenesis. The pharmacologic action of most of these drugs, however, is not necessarily limited to downregulaton of A2. Many ACEI, especially those containing the sulfhydryl (SH group), possess antioxidant or metalloprotease inhibitory properties per se. These experimental and retrospective data justify clinical testing of these drugs in appropriate randomized trials. Several such trials are currently in process. If these trials confirm the experimental and retrospective studies, these agents will provide a significant contribution to the therapeutic treatment of many malignancies in humans.
Angiotensin II↗
Radiation induces endothelial dysfunction in murine intestinal arterioles via enhanced production of reactive oxygen species.
OBJECTIVE: Endothelial dysfunction and vascular dysregulation contribute to the pathological effects of radiation on tissues. The objectives of this study were to assess the acute effect of irradiation on acetylcholine (Ach)-induced dilation of gut submucosal microvessels. METHODS AND RESULTS: Rats were exposed in vivo to 1 to 9 cGy in 3 fractions per week on alternate days for 3 successive weeks for a total dose of up to 2250 cGy. Submucosal microvessels were isolated after varying levels of irradiation. Diameters of isolated vessels were measured using videomicroscopy, and the dose-response relationship to Ach was determined. Dihydroethidine and 2', 7'-dichlorodihydrofluorescein diacetate fluorescent probes were used to assess reactive oxygen species (ROS) production. After constriction (30% to 50%) with endothelin, dilation to graded doses of Ach (10(-9)-10(-4) M) was observed in control vessels (maximal dilation [MD] 87+/-3%; n=7). However, Ach-induced dilation was reduced in vessels from irradiated rats (MD=3+/-9%; n=7; P= or <0.05 versus controls). Significant increases in superoxide and peroxides were observed in irradiated microvessels. Irradiated microvessels pretreated with superoxide dismutase-mimetic demonstrated significant improvement in Ach-induced vasodilation compared with irradiation alone, suggesting that superoxide contributes to impaired dilation to Ach after irradiation. CONCLUSIONS: Radiation induces acute microvascular dysfunction in the resistance arterioles of the intestine. Enhanced ROS contribute to this dysfunction and therefore may represent a novel therapeutic target to minimize radiation toxicity in the gut.
Acetylcholine↗
Medicine. Modulation of radiation injury.
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Animals↗
Impact of angiotensin II type 2 receptor blockade on experimental radiation nephropathy.
In the rat, blockade of angiotensin II type 1 receptors diminishes the functional changes that occur after kidney irradiation. It has been hypothesized that some of the beneficial effects of angiotensin II type 1 blockers in renal disease are caused by a rise in angiotensin II that stimulates the angiotensin II type 2 receptor. If this hypothesis applied in this model, blockade of the type 2 receptor should exacerbate radiation nephropathy and/or counteract the beneficial effects of type 1 receptor blockade. To assess this hypothesis, rats were given total-body irradiation plus bone marrow transplantation and then treated for 12 weeks with a type 1 receptor blocker (L158,809), a type 2 blocker (PD123319), both blockers, or no blockers. Rats were assessed for renal function (proteinuria, hypertension, azotemia) and renal failure for up to 62 weeks. Contrary to the hypothesis, the type 2 blocker alone produced a temporary delay in the development of radiation nephropathy, and it substantially enhanced the efficacy of the type 1 blocker. This implies that both type 1 and type 2 angiotensin receptors need to be blocked to achieve the maximum level of prophylaxis of radiation nephropathy. We speculate that the beneficial effect of the angiotensin II type 2 receptor blocker is due to a reduction in radiation-induced renal cell proliferation or fibrosis.
Angiotensin II Type 1 Receptor Blockers↗
Models for evaluating agents intended for the prophylaxis, mitigation and treatment of radiation injuries. Report of an NCI Workshop, December 3-4, 2003.
To develop approaches to prophylaxis/protection, mitigation and treatment of radiation injuries, appropriate models are needed that integrate the complex events that occur in the radiation-exposed organism. While the spectrum of agents in clinical use or preclinical development is limited, new research findings promise improvements in survival after whole-body irradiation and reductions in the risk of adverse effects of radiotherapy. Approaches include agents that act on the initial radiochemical events, agents that prevent or reduce progression of radiation damage, and agents that facilitate recovery from radiation injuries. While the mechanisms of action for most of the agents with known efficacy are yet to be fully determined, many seem to be operating at the tissue, organ or whole animal level as well as the cellular level. Thus research on prophylaxis/protection, mitigation and treatment of radiation injuries will require studies in whole animal models. Discovery, development and delivery of effective radiation modulators will also require collaboration among researchers in diverse fields such as radiation biology, inflammation, physiology, toxicology, immunology, tissue injury, drug development and radiation oncology. Additional investment in training more scientists in radiation biology and in the research portfolio addressing radiological and nuclear terrorism would benefit the general population in case of a radiological terrorism event or a large-scale accidental event as well as benefit patients treated with radiation.
Animals↗
Successful treatment of radiation nephropathy with angiotensin II blockade.
PURPOSE: The aim of this report is to document the successful treatment of radiation nephropathy. METHODS: Clinical case report with statistical analysis of evolution of kidney function. RESULTS: A case of radiation nephropathy was found in a kidney transplant recipient whose kidney transplant had been irradiated with 750 cGy 23 years previously. Use of the angiotensin II blocker, losartan, was associated with significant stabilization of the kidney function. CONCLUSION: Radiation nephropathy can be successfully treated. Other normal-tissue radiation injuries may also be treatable.
Adult↗
Using high spectral and spatial resolution bold MRI to choose the optimal oxygenating treatment for individual cancer patients.
We evaluate whether high spectral and spatial resolution (HiSS) BOLD MRI can correctly rank the effects of three tumor-oxygenating treatments on radiosensitivity in BA1112 rhabdomyosarcomas (n = 5). Significant decreases in spectral linewidth predict that treatment with carbogen gas combined with a perfluorocarbon emulsion will increase radiosensitivity more than either treatment alone, which agrees with the known effects of these treatments on hypoxic fraction. High-resolution maps show that tumor response to each treatment is spatially heterogeneous, and that there is a paradoxical response to the treatments in 7-12% of tumor pixels. Because HiSS MRI emphasizes changes in necrotic and/or hemorrhagic regions, it is more sensitive to oxygenation changes compared to conventional MRI. These results demonstrate that HiSS MRI is a practical, noninvasive method that could be used to choose the treatment that maximizes the size and extent of increases in tumor oxygenation for individual patients.
Animals↗
Pharmacological intervention to prevent or ameliorate chronic radiation injuries.
Until the 1990s, chronic radiation-induced normal-tissue injury was viewed as being due solely to the delayed mitotic death of parenchymal or vascular cells; these injuries were held to be inevitable, progressive, and untreatable. It is now clear that parenchymal and vascular cells are active participants in the response to radiation injury rather than passive observers dying as they attempt to divide. This offers fundamentally new approaches to radiation injury because it allows for the possibility of pharmacological interventions directed at modulating steps in the cascade of events leading to expression of injury. Such interventions would be relevant to both cancer patients and victims of radiation accidents. Prophylaxis and treatment of chronic radiation injuries have been experimentally shown in multiple organ systems (eg, lung, kidney, soft tissue) and with fundamentally different pharmacological agents (eg, corticosteroids, angiotensin-converting enzyme inhibitors, pentoxifylline, superoxide dismutase). For the most part, this has been achieved using clinically relevant radiation and drug schedules and with agents that have already been approved for human use. Unfortunately, assessment of the utility of these agents for clinical use has been minimal, and there are no established mechanisms for any of the experimental or clinical successes. Clinical development of pharmacological approaches to modification of chronic radiation injuries could lead to significant improvement in survival and quality of life for radiotherapy patients and for victims of radiation accidents or nuclear terrorism.
Chronic Disease↗
Critiquing unpublished theories.
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Government Agencies↗
Molecular and cellular biology of moderate-dose (1-10 Gy) radiation and potential mechanisms of radiation protection: report of a workshop at Bethesda, Maryland, December 17-18, 2001.
Exposures to doses of radiation of 1-10 Gy, defined in this workshop as moderate-dose radiation, may occur during the course of radiation therapy or as the result of radiation accidents or nuclear/radiological terrorism alone or in conjunction with bioterrorism. The resulting radiation injuries would be due to a series of molecular, cellular, tissue and whole-animal processes. To address the status of research on these issues, a broad-based workshop was convened. The specific recommendations were: (1) RESEARCH: Identify the key molecular, cellular and tissue pathways that lead from the initial molecular lesions to immediate and delayed injury. The latter is a chronic progressive process for which postexposure treatment may be possible. (2) Technology: Develop high-throughput technology for studying gene, protein and other biochemical expression after radiation exposure, and cytogenetic markers of radiation exposure employing rapid and accurate techniques for analyzing multiple samples. (3) Treatment strategies: Identify additional biological targets and develop effective treatments for radiation injury. (4) Ensuring sufficient expertise: Recruit and train investigators from such fields as radiation biology, cancer biology, molecular biology, cellular biology and wound healing, and encourage collaboration on interdisciplinary research on the mechanisms and treatment of radiation injury. Communicate knowledge of the effects of radiation exposure to the general public and to investigators, policy makers and agencies involved in response to nuclear accidents/events and protection/treatment of the general public.
Animals↗
Radiobiology of nuclear terrorism: report on an interagency workshop (Bethesda, MD, December 17-18, 2001).
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Dose-Response Relationship, Radiation↗
Spectrally inhomogeneous BOLD contrast changes detected in rodent tumors with high spectral and spatial resolution MRI.
MRI detects changes in blood-oxygenation-level dependent (BOLD) contrast in tumors caused by tumor oxygenating agents. These changes can be used to guide the design of improved tumor oxygenating treatments (TOXs). The conventional approach to detection of BOLD effects assumes that the water resonance is a single, homogeneously broadened Lorentzian line, and that changes in the T2* of this line owing to changes in deoxyhemoglobin are spectrally homogeneous. This model may not adequately describe BOLD contrast changes in complex water resonances that are often detected in tumors. The present work investigated: (a) whether changes in the water resonance in very small voxels caused by tumor oxygenating agents are spectrally inhomogeneous; and (b) whether high spectral and spatial resolution (HiSS) MRI of the water and fat resonances detects these changes more accurately than conventional gradient-recalled echo (GRE) imaging. Carbogen (95% oxygen, 5% CO2) was used to increase tumor oxygenation. In two tumor models [mammary adenocarcinoma (R3230Ac; n=5) and rhabdomyosarcoma (BA1112; n=5)] proton signals were often complex and inhomogeneously broadened. Spectrally inhomogeneous changes during carbogen breathing occurred in at least 10% of the R3230AC tumor voxels that responded to carbogen and 18% of BA1112 tumor voxels. The largest changes during carbogen breathing in many voxels occurred at frequencies that were significantly different from the frequency of the primary water peak. Carbogen-induced changes in proton T2* detected by simulated GRE and HiSS differed by more than 75% in 67% of voxels in R3230Ac tumors and in 65% of voxels in BA1112 tumors. The spectrally inhomogeneous effects of tumor oxygenating agents may reflect changes in sub-voxelar microenvironements and thus may be important for accurate evaluation of the effects of therapy.
Adenocarcinoma↗
The renin-angiotensin system in experimental radiation nephropathy.
Irradiation of the kidneys is followed by a well-defined sequence of changes leading eventually to kidney failure. In the rat, inhibition of angiotensin-converting enzyme or blockade of angiotensin II receptors can prevent the structural and functional changes that occur after kidney irradiation. These interventions are particularly effective between 3 and 10 weeks after irradiation. However, in a series of studies with the rat model we failed to find any evidence that the renin-angiotensin system (RAS) is activated in the first 10 weeks after kidney irradiation. First, if the RAS was activated during this interval, one would expect hypertension followed by proteinuria and azotemia. However, hypertension is significant only at the end of this period and is preceded by significant proteinuria and azotemia. This evolution is not in favor of an obviously activated RAS during the 3- to 10-week postirradiation interval that is critical for interventions aimed at the RAS. Second, plasma renin activity and active plasma renin protein concentrations are not significantly increased over the first 10 weeks after irradiation. Third, whole-blood and intrarenal angiotensin II levels are not increased and may even be decreased over this interval. This last observation is particularly important because the assay used is sensitive enough to detect the effects of dietary salt manipulation. We hypothesize that even the normal activity of the RAS contributes to injury after kidney irradiation, possibly by supporting the proliferation of cells that carry potentially lethal radiation injuries.
Animals↗
Loss of albumin and megalin binding to renal cubilin in rats results in albuminuria after total body irradiation.
The role of the renal apical brush-border membrane (BBM) endocytic receptors cubilin and megalin in the onset of albuminuria in rats exposed to a single dose of total body irradiation (TBI) has been investigated. Albuminuria was evident as immunoblot (IB) analysis of the urine samples from TBI rats revealed excretion of large amounts of albumin. IB analysis of the BBM proteins did not reveal any significant changes in cubilin or megalin levels, but (125)I-albumin binding to BBM from TBI rats declined by 80% with a fivefold decrease (from 0.5 to 2.5 microM) in the affinity for albumin. IB analysis of cubilin from the BBM demonstrated a 75% loss when purified using albumin, but not intrinsic factor (IF)-cobalamin (Cbl) ligand affinity chromatography. Immunoprecipitation (IP) of Triton X-100 extract of the BBM with antiserum to cubilin followed by IB of the immune complex with an antiserum to megalin revealed a 75% loss of association between megalin and cubilin. IP studies with antiserum to cubilin or megalin and IB with antiserum to the cation-independent mannose 6-phosphate/insulin-like growth factor II-receptor (CIMPR) revealed that CIMPR interacted with both cubilin and megalin. In addition, TBI did not disrupt the association of CIMPR with either cubilin or megalin in BBM. These results suggest that albuminuria noted in TBI rats is due to selective loss of albumin and megalin, but not CIMPR or IF-Cbl binding by cubilin. Furthermore, these results also suggest that albumin and IF-Cbl binding to cubilin occur at distinct sites and that in the rat renal BBM, CIMPR interacts with both cubilin and megalin.
Albuminuria↗