Effect of Ionizing Radiation on Immunity

Ionizing radiation has a deleterious effect on the immunity mechanism, particularly when large but sublethal doses are applied over a short period of time. The hematopoietic system is extremely sensitive, and a fall in the lymphocytes is one of the most characteristic manifestations. The normal balance of the microflora of the intestinal and respiratory tracts is disturbed, which results in a bacteremia and may lead to death of the host. Active immunity is seriously interfered with if the irradiation occurs shortly before the injection of an antigen. There is also reduced resistance to pathogenic micro-organisms, which may lead to fatal infections. Prolonged irradiation at low levels does not seem to affect immunity adversely. Active immunization should be carried out well in advance of exposure to radiation, and supportive treatment commenced immediately after exposure to large doses.     

Integrin Signalling and the Cellular Response to Ionizing Radiation

Cell survival and cycling in mammalian cells are both greatly affected by ionizing radiation and are both strictly controlled by integrated integrin-mediated adhesion to extracellular matrix (ECM) proteins and by binding of growth factors to their cognate receptors. Recent emerging findings show a diverse panel of integrin-dependent signals that are channelled into the regulation and modification of the cellular response to ionizing radiation. Cell adhesion-mediated radioresistance and alteration of DNA damage-induced cell cycle arrest in cells attached to the ECM can be linked to focal adhesion protein signalling. This review summarizes the latest radiobiological and radiooncological findings about integrins and their signal transduction pathways.     

Ionizing Radiation as an Industrial Health Problem

Ionizing radiation, first as x-rays, later in natural form, was discovered in Europe in the late 1890''s. Immediate practical uses were found for these discoveries, particularly in medicine. Unfortunately, because of the crude early equipment and ignorance of the harmful effects of radiation, many people were injured, some fatally. Because of these experiences, committees and regulatory bodies were set up to study the problem. These have built up an impressive fund of knowledge useful in radiation protection.With the recent development of the peaceful uses of atomic energy, sources of radioactivity have appeared cheaply and in abundance. A rapidly growing number are finding industrial application. Because of their potential risk to humans, the industrial physician must acquire new knowledge and skills so that he may give proper guidance in this new realm of preventive medicine.The Radiation Protection Program of one such industry, the Hydro-Electric Power Commission of Ontario, is summarized.     

Effects of Ionizing Radiation on Bacterial DNA-membrane Complexes

THE model proposed by Alper¹ for lethal radiation damage to cells is based on inferential evidence that there are two important sites of damage by ionizing radiation. At one site, damage referred to as type “N” is associated with a low oxygen enhancement ratio (OER) and is probably to nucleic acid, while at the other site, type “O” damage is associated with a considerably higher oxygen enhancement value and is to a non-nucleic acid target. The model demands that the two values of OER are respectively less and greater than that observed for the overall lethal effect. More recently² Alper reviewed further inferential evidence³ that cell membranes are the site of type O damage, though there may be subsequent interaction with the lesions following energy deposition in DNA⁴.     

电离辐射诱导基因的研究进展

电离辐射诱导基因是一类受电离辐射调控表达的基因,其表达随辐射条件和所处生理环境的不同呈现复杂多变的特征。电离辐射诱导基因参与细胞内各种代谢途径,在细胞周期调控、细胞生长调节、细胞凋亡、DNA损伤修复中发挥着重要的作用。介绍了电离辐射诱导基因的种类、功能,及其引起的生物效应的分子机制及应用。     

Consequences of Low Dose Ionizing Radiation Exposure on the Hippocampal Microenvironment

The response of the brain to irradiation is complex, involving a multitude of stress inducible pathways that regulate neurotransmission within a dynamic microenvironment. While significant past work has detailed the consequences of CNS radiotherapy following relatively high doses (≥ 45 Gy), few studies have been conducted at much lower doses (≤ 2 Gy), where the response of the CNS (like many other tissues) may differ substantially from that expected from linear extrapolations of high dose data. Low dose exposure could elicit radioadaptive modulation of critical CNS processes such as neurogenesis, that provide cellular input into hippocampal circuits known to impact learning and memory. Here we show that mice deficient for chemokine signaling through genetic disruption of the CCR2 receptor exhibit a neuroprotective phenotype. Compared to wild type (WT) animals, CCR2 deficiency spared reductions in hippocampal neural progenitor cell survival and stabilized neurogenesis following exposure to low dose irradiation. While radiation-induced changes in microglia levels were not found in WT or CCR2 deficient animals, the number of Iba1+ cells did differ between each genotype at the higher dosing paradigms, suggesting that blockade of this signaling axis could moderate the neuroinflammatory response. Interestingly, changes in proinflammatory gene expression were limited in WT animals, while irradiation caused significant elevations in these markers that were attenuated significantly after radioadaptive dosing paradigms in CCR2 deficient mice. These data point to the importance of chemokine signaling under low dose paradigms, findings of potential significance to those exposed to ionizing radiation under a variety of occupational and/or medical scenarios.     

The Influence of Ionizing Radiation on Itraconazole in the Solid State

The aim of this study was to investigate the ionizing radiation effects, in the form of an electron beam, on itraconazole (ITR) in the solid phase. It was found that the ITR, under the influence of a standard 25 kGy dose of radiation used for the sterilization of drug substances, decomposed at 0.4%. Moreover, a gentle change of colour and a decrease in melting point does not exceed pharmacopoeial standards causing that ITR can be sterilized by radiation method. The use of high 400 kGy radiation doses resulted in a 6.5% decomposition of the ITR and eight radiodegradation products were found. However, with the exception of differential scanning calorimetry (DSC), the X-ray diffraction, Fourier transform infrared spectroscopy (FT-IR) and ultraviolet-visible (UV-vis) methods showed no changes in the form and the morphology of the crystals. The structures of all those compounds were investigated. It was confirmed that the ITR decomposition takes place by dehalogenation (one of Cl atom elimination), the oxidation in isobutyl residue (beside the triazole ring) and C-O bond rupture.KEY WORDS: antifungal azole, DSC, itraconazole, product radiolysis, radiation sterilization     

Directed Evolution of Ionizing Radiation Resistance in Escherichia coli

We have generated extreme ionizing radiation resistance in a relatively sensitive bacterial species, Escherichia coli, by directed evolution. Four populations of Escherichia coli K-12 were derived independently from strain MG1655, with each specifically adapted to survive exposure to high doses of ionizing radiation. D₃₇ values for strains isolated from two of the populations approached that exhibited by Deinococcus radiodurans. Complete genomic sequencing was carried out on nine purified strains derived from these populations. Clear mutational patterns were observed that both pointed to key underlying mechanisms and guided further characterization of the strains. In these evolved populations, passive genomic protection is not in evidence. Instead, enhanced recombinational DNA repair makes a prominent but probably not exclusive contribution to genome reconstitution. Multiple genes, multiple alleles of some genes, multiple mechanisms, and multiple evolutionary pathways all play a role in the evolutionary acquisition of extreme radiation resistance. Several mutations in the recA gene and a deletion of the e14 prophage both demonstrably contribute to and partially explain the new phenotype. Mutations in additional components of the bacterial recombinational repair system and the replication restart primosome are also prominent, as are mutations in genes involved in cell division, protein turnover, and glutamate transport. At least some evolutionary pathways to extreme radiation resistance are constrained by the temporally ordered appearance of specific alleles.A survey of bacteria and archaea identifies 11 phyla that contain species with unusually high resistance to the lethal effects of ionizing radiation (IR). These phyla are not closely related to each other and do not share a common lineage, and all include genera that are considered radiosensitive (9). The existence of so many unrelated and isolated radioresistant species in the phylogenetic tree argues that the molecular mechanisms that protect against IR-induced damage evolved independently in these organisms, suggesting that at least some species have the capacity to acquire radioresistance through evolutionary processes if they are subjected to appropriate selective pressure.The first of these species to be discovered, and the best studied to date, is the bacterium Deinococcus radiodurans. The molecular basis of the extraordinary radioresistance of Deinococcus has not been elucidated, but well-constructed proposals abound. Radioresistance has variously been attributed to the condensed structure of the nucleoid (29, 40, 56), the elevated levels of Mn ion present in the cytosol as a mechanism to control protein oxidation (11, 12), a specialized RecA-independent DNA repair process (54), and other species attributes (9). Radioresistance in Deinococcus is probably mechanistically related to desiccation resistance derived from evolution in arid environments (37, 45), although this may not be the origin of the phenotype in all relevant species (9).An understanding of the genetic underpinnings of bacterial radiation resistance holds promise for yielding insights into the mechanistic basis of radiation toxicity, along with the potential for new approaches to facilitate recovery from radiation injury in other organisms, including humans. To better define the genetic, biochemical, and physiological characteristics most important for radioresistance, we employed a strategy to allow the cells to inform us. In brief, we generated radioresistant variants of radiosensitive bacteria and defined the genetic changes underlying the new phenotype.In 1946, Evelyn Witkin established that it was possible to increase the resistance of Escherichia coli B to DNA damage (50). She exposed cultures to high doses of UV light, killing most of the population and selecting for variants better able to tolerate UV. In the 6 decades since the Witkin report, additional investigators have repeated this result, demonstrating that iterative cycles of high-dose exposure to a DNA damaging agent can heritably enhance a culture''s ability to tolerate that DNA damaging agent. Increases in IR resistance have been reported for E. coli (17), Salmonella enterica serovar Typhimurium (14), and Bacillus pumulis (44), organisms that are otherwise considered radiosensitive. Davies and Sinskey (14) showed that for S. enterica serovar Typhimurium LT2, the number of cycles of exposure and recovery correlates with the level of radioresistance achieved. After 84 cycles, they generated a strain displaying inactivation kinetics similar to that of Deinococcus radiodurans, with a D₁₀ value (the dose needed to inactivate 90% of the population) 200-fold higher than that of the parental strain.For this study, we expanded on these earlier studies by independently generating four IR-resistant populations of Escherichia coli K-12 MG1655 (4). Our effort included an important innovation relative to the earlier studies—we characterized the evolved populations with an experimental program that included the complete genomic resequencing of multiple strains purified from three of the populations, taking advantage of new sequencing technologies. The result is an increasingly detailed data set—based on a single robust model system—that allows us to (i) explore the molecular basis of radiation resistance in bacteria and (ii) test current hypotheses and search for novel mechanisms of radiation resistance.     

Cardiovascular Risks Associated with Low Dose Ionizing Particle Radiation

Previous epidemiologic data demonstrate that cardiovascular (CV) morbidity and mortality may occur decades after ionizing radiation exposure. With increased use of proton and carbon ion radiotherapy and concerns about space radiation exposures to astronauts on future long-duration exploration-type missions, the long-term effects and risks of low-dose charged particle irradiation on the CV system must be better appreciated. Here we report on the long-term effects of whole-body proton (¹H; 0.5 Gy, 1 GeV) and iron ion (⁵⁶Fe; 0.15 Gy, 1GeV/nucleon) irradiation with and without an acute myocardial ischemia (AMI) event in mice. We show that cardiac function of proton-irradiated mice initially improves at 1 month but declines by 10 months post-irradiation. In AMI-induced mice, prior proton irradiation improved cardiac function restoration and enhanced cardiac remodeling. This was associated with increased pro-survival gene expression in cardiac tissues. In contrast, cardiac function was significantly declined in ⁵⁶Fe ion-irradiated mice at 1 and 3 months but recovered at 10 months. In addition, ⁵⁶Fe ion-irradiation led to poorer cardiac function and more adverse remodeling in AMI-induced mice, and was associated with decreased angiogenesis and pro-survival factors in cardiac tissues at any time point examined up to 10 months. This is the first study reporting CV effects following low dose proton and iron ion irradiation during normal aging and post-AMI. Understanding the biological effects of charged particle radiation qualities on the CV system is necessary both for the mitigation of space exploration CV risks and for understanding of long-term CV effects following charged particle radiotherapy.     

IRM-2近交系小鼠对电离辐射抗性的研究

目的观察IRM-2小鼠对电离辐射的耐受性.方法分析测定了IRM-2小鼠对137Csγ射线的LD50及经4.0Gy137Csγ射线照射后不同时间外周血白细胞、骨髓有核细胞总数、骨髓细胞DNA含量和脾结节的变化,并与亲代小鼠ICR和615进行了比较.结果用不同剂量的137Csγ射线照射后,IRM-2小鼠对γ射线的LD50比ICR和615小鼠分别高1.73～1.57Gy和1.44Gy;外周血白细胞数和骨髓有核细胞总数、骨髓细胞DNA含量下降的幅度小且恢复得快;CFU-S的增加也较ICR和615小鼠明显.结论IRM-2小鼠比一般的纯系和杂交品系小鼠具有更强的辐射抗性.     

Dynamics of Tumor Hypoxia in Response to Patupilone and Ionizing Radiation

Tumor hypoxia is one of the most important parameters that determines treatment sensitivity and is mainly due to insufficient tumor angiogenesis. However, the local oxygen concentration in a tumor can also be shifted in response to different treatment modalities such as cytotoxic agents or ionizing radiation. Thus, combined treatment modalities including microtubule stabilizing agents could create an additional challenge for an effective treatment response due to treatment-induced shifts in tumor oxygenation. Tumor hypoxia was probed over a prolonged observation period in response to treatment with different cytotoxic agents, using a non-invasive bioluminescent ODD-Luc reporter system, in which part of the oxygen-dependent degradation (ODD) domain of HIF-1α is fused to luciferase. As demonstrated in vitro, this system not only detects hypoxia at an ambient oxygen concentration of 1% O₂, but also discriminates low oxygen concentrations in the range from 0.2 to 1% O₂. Treatment of A549 lung adenocarcinoma-derived tumor xenografts with the microtubule stabilizing agent patupilone resulted in a prolonged increase in tumor hypoxia, which could be used as marker for its antitumoral treatment response, while irradiation did not induce detectable changes in tumor hypoxia. Furthermore, despite patupilone-induced hypoxia, the potency of ionizing radiation (IR) was not reduced as part of a concomitant or adjuvant combined treatment modality.