全身辐射后免疫器官、肾脏和甲状腺损伤规律及PET/CT可对其损伤进行快速评估
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摘要
背景
目前,核技术发展迅速,并已广泛应用于国民经济的各个领域。在核发电、农业育种、物理探矿、辐射加工和灭菌、疾病治疗、考古及科学研究等领域的应用,已取得了极大的经济效益和社会效益,促进了人类文明的进步。随着科学技术的不断发展,核技术应用的安全性也明显提高。但由于管理不善、违规操作规程等原因,发生核辐射事故并造成人员伤亡和环境污染的后果是灾难性的,如类似于苏联切尔诺贝利、美国三哩岛及日本福岛核泄露及日本广岛原子弹爆炸等。因此,全世界都在为辐射防护做出不懈的努力,而辐射防护的的管理依然是建立在电离辐射与活体组织之间相互作用(1)及特异的生物剂量测定法上。为了应对大规模辐射事故后伤员及时、合理及有效的救治,目前研究主要是集中在伤员所吸收的辐射剂量的测定。传统辐射剂量测定法(外周血淋巴细胞计数、双着丝粒染色体测定、染色体过早浓缩、微核)存在耗时、费力及非均一性等特点,而最新方法(遗传学技术(体细胞突变血型糖蛋白A、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶)、基因表达测定法及蛋白标记物(g-H2AX及C反应蛋白))依然未得到统一的认可。因此,有必要探索更简单、准确、高通量且能全面反映组织损伤程度的新方法。
目的
这项研究主要是探讨全身辐射后免疫器官、肾脏和甲状腺的损伤规律及PET/CT可否对其损伤进行快速评估,为临床急性辐射病的诊断及救治提供实验依据。
材料及方法
这项研究得到了南方医科大学动物保护及使用委员会的批准(License number SCXK (Yue)2006-0015)。成年未阉割的西藏小型猪(体重21.16±5.54kg)由南方医科大学动物中心提供并在标准的实验室条件下圈养,它们可以自由摄入食物和水。
将48头已麻醉(Sumianxin Ⅱ:0.15mL/kg)的西藏小型猪按照辐射剂量随机分成一个对照组(0Gy)和五个实验组(2Gy,5Gy,8Gy,11Gy和14Gy),将麻醉后的实验组动物固定于放疗中心操作台上,接受8Mv X线(等中心的)线性加速器、辐射剂量率为255cGy/min的一次性全身辐射,所有的西藏小型猪在麻醉的条件下分别于各剂量全身照射前与照射后6、24和72小时接受18F-FDG-PET/CT检查,同时收集对照组及各剂量全身照射后6、24及72小时组西藏小型猪的免疫器官、肾脏及甲状腺等组织进行组织学检测(光镜和电镜)和流式细胞仪检测凋亡的淋巴细胞,同时也将收集的外周血进行分类计数、肾及甲状腺功能检测。
我们选择五个剂量组(2,5,8,11和14Gy),在人体这几个辐射剂量都有其自身的医学意义。辐射剂量从2到14Gy主要引起造血免疫系统及胃肠道系统的损伤。大规模急性辐射事故后,吸收不同辐射剂量的病人需要不同类型的医学干预和护理。接受2Gy以下的辐射一般不会引起急性效应因此不需要特别地支持治疗,在2-5Gy之间需要立即使用抗生素、血小板及细胞因子等综合治疗,在5-8Gy或者8-11Gy及时骨髓移植是挽救生命最佳的选择,而大于11Gy(14Gy)由于致命性的胃肠道的损伤目前是无法挽救的。我们选择2、5、8、11及14Gy这五个剂量组是因为能迅速且精确测定这些剂量有助于辐射伤员合理有效的救治。我们选择照射后6、24及72小时三个观察时间点是基于一方面潜伏期(辐射暴露到症状开始)对于医学干预是至关重要的,另一方面急性辐射综合症的症状一般在照射后几小时到几天内出现。
18F-FDG-PET/CT是一种根据良、恶性组织生物化学代谢差异的非侵袭性诊断技术,它广泛用于许多恶性肿瘤分期及分级并用于恶性肿瘤治疗后的检测。但是,作为葡萄糖类似物的18F-FDG在正常及良性组织中摄取也存在。此外,18F-FDG-PET/CT被证实也能检测炎症及感染过程。本实验利用该技术来研究不同剂量全身照射后各组织损伤后18F-FDG摄取的差异,以此来推断组织损伤、剂量及18F-FDG摄取三者之间的内在联系。
结果
一般观察：照射后72小时内各剂量组未见西藏小型猪死亡。照射后西藏小型猪精神状态不佳,食欲减退,懒怠,活动减少,皮肤红斑；随辐射剂量增加,呕吐和腹泻时间出现更早,皮肤红斑的面积也更大。
外周血细胞计数：不同剂量照射后,西藏小型猪外周血白细胞计数于照射后6小时出现短暂性升高,于2Gy达最大值(12.98±0.23)；随后迅速下降,于14Gy照射后72小时下降至最低值(1.28±0.25)。全身照射后外周血淋巴细胞数目迅速下降,于14Gy照射后72小时达最低值(0.065±0.029)。
脾脏标准摄取值(SUV)：采用单因素方差分析(one-way ANOVA)检验和一般线性模型(repeated measures)分析,Mauchly球形检验统计量W=0.740P=0.665不拒绝球形假设。各剂量间有显著性差异(F=107.445P=0.000),全身辐射前对照组与实验组间无显著性差异(F=0.375P=0.856),四个时间点间差异有显著性意义(F=306.379P=0.000),各时间点多重比较显示四个时间点间均有显著差异(P≤0.001)。剂量与时间点间存在交互作用(F=32.894P=0.000),11Gy照射后6小时交互效应最显著。用线性相关分析评估了不同剂量全身照射后6、24和72小时脾脏SUV值,其“辐射剂量”不服从正态分布,Spearman's相关系数分别是r=0.94P<0.01,0.91P<0.01,0.82P<0.01,且照射后6小时脾脏平均SUV与辐射剂量显示出清晰且显著的阳性相关。PET/CT影像学特征：正常脾脏18F-FDG摄取非常少且均一,照射后6小时脾脏18F-FDG吸收随剂量增加而显著增加,照射后24及72小时18F-FDG摄取也随剂量有所增加,但并不显著。
肾脏标准摄取值(SUV)：采用以上统计学分析,Mauchly球形检验统计量左侧：W=0.400P=0.081,右侧：W=0.387P=0.071,均拒绝球形假设。各照射剂量间存在显著性差异(左侧：F=225.289,P=0.000；右侧：F=114.942,P=0.000),四个时间点间差异有显著性意义(左侧：F=195.210,P-0.000；右侧：F=188.081,,P=0.000),各时间点多重比较四个时间点间无显著差异(P≥.05)。剂量与时间间存在交互作用(左侧：F=44.008.,P=0.000；右侧：F=42.223,P=0.000),交互效应最显著的均是14Gy照射后72小时。PET/CT影像学特征：对照,2,5及8Gy组18F-FDG的摄取非常少且均匀；而在11及14Gy组,随着观察时间的延长,双侧肾实质18F-FDG吸收值显著增高。
光镜及电镜：光镜下观察到不同剂量照射后胸腺、脾脏、淋巴结等免疫组织淋巴细胞损伤均出现基本相似的病理变化,经历了照射后6小时各组织淋巴细胞的死亡期(坏死与凋亡)、24小时淋巴细胞碎片的清除期及72小时淋巴细胞枯竭期三个病理发展阶段,这在胸腺皮质、脾脏白髓及淋巴结的生发中心表现最为突出。14Gy组24及72小时淋巴结切片见淋巴结结构遭到破坏。电镜下观察到照射后6小时见大量凋亡的淋巴细胞,核膜完整,染色质浓集,部分细胞的核碎片和胞浆成分形成凋亡小体,随照射剂量的增加,凋亡的淋巴细胞数量增多,吞噬现象也明显增多；24小时淋巴细胞数量明显减少,吞噬细胞数量显著增多,每个吞噬细胞中均可见到3-7个凋亡的淋巴细胞或细胞碎片,14Gy组淋巴结中见点状及片状坏死灶；72小时凋亡的淋巴细胞已难见到,随剂量增加,组织切片呈空虚状,网状细胞线粒体及内质网明显空泡化。光镜下观察到高剂量(11和14Gy)见局部淤血及出血,其明确的改变是在高剂量照射后24,72小时,尤其是接受14Gy照射组出现急性出血,肾间质炎症细胞的侵润,肾小管细胞的变性和坏死及管型的形成,肾小球仅见血管的充血及内皮细胞的肿胀；电镜下观察到显著的改变是11Gy照射后6小时,肾小球上皮细胞及血管内皮细胞异染色质明显增多；肾小管上皮细胞变性改变最早见于8Gy照射后6小时,异染色质凝集及聚集,线粒体及内质网扩张及大量溶酶体结构及脂滴。正常的甲状腺由大小均一的滤泡组成,其内充满均匀的胶质并由立方型滤泡上皮组成；全身照射后6小时,我们能观察到滤泡内充填浓的、深染的胶质及新形成的吸收空泡,其立方型滤泡上皮变成柱状型上皮；照射后24小时,甲状腺由大小不同的滤泡组成,其内充满薄的、淡然的胶质及混合型滤泡上皮；照射后72小时,甲状腺滤泡内少甚至无胶质充填,其周围由立方型上皮组成；三个时间点均能观察到间质不同程度血管充血、肿胀及炎症细胞的侵润(许多单核细胞及淋巴细胞),这些病理改变随剂量增加变得更严重。电镜下,正常组我们能观察到立方、柱状上皮细胞及显著的微绒毛,随着剂量的增加,微绒毛从正常到薄再到无,缝隙连接也逐渐变模糊,线粒体肿胀及内质网扩张,高剂量下我们能在核周围观察到异染色质聚集及浓缩。
不同剂量照射后脾脏、胸腺和淋巴结淋巴细胞的凋亡率情况。Mauchly球形检验统计量W=0.693P=0.133不拒绝球形假设,各剂量组间有显著性差异(F=251.87P=0.000),三个时间点间差异有显著性意义(F=530.24P=0.000,),剂量与时间间存在交互作用(F=145.36P=0.000),脾脏淋巴细胞凋亡率交互效应最显著是14Gy照射后6小时。Mauchly球形检验统计量W=0.426P=0.009,拒绝球形假设。各剂量间存在显著性差异(F=1379.847P=0.000),三个时间点间差异有显著性意义(F=221.711P=0.000),剂量与时间间存在交互作用(F=23.471P=0.000),胸腺淋巴细胞凋亡率交互效应最明显的是14Gy照射后24小时。Mauchly球形检验统计量W=0.978P=0.883不拒绝球形假设不拒绝球形假设,各剂量间存在显著性差异(F=133.704P=0.000)三个时间点间差异有显著性意义(F=179.188P=0.000),剂量与时间间存在交互作用(F=22.569P=0.000),淋巴结淋巴细胞凋亡率交互效应最明显的是11Gy照射后24小时。
肾功能测定主要包括肌酐及尿素氮：Mauchly球形检验统计量W=0.867P=0.456不拒绝球形假设,各剂量间存在显著性差异(F=54.308P=0.000),三个时间点间差异有显著性意义(F=9.527P=0.000),剂量与时间间存在交互作用(F=7.352P=0.000),交互作用最明显的是14Gy照射后24小时的尿素氮。Mauchly球形检验统计量W=0.840P=0.384不拒绝球形假设,各剂量间存在显著性差异(F=54.308P=0.000),三个时间点间差异有显著性意义(F=104.753P=0.000),剂量与时间间存在交互作用(F=20.842P=0.000),交互效应最明显的是14Gy照射后72小时的肌酐。
全身照射后甲状腺重量及功能的改变情况。Mauchly球形检验统计量W=0.962P=0.808不拒绝球形假设。各剂量间存在差异(F=4.831P=0.012),三个时间点间差异有显著性意义(F=12.482P=0.000),甲状腺重量中剂量与时间间不存在交互作用(F=1.685P=1.43)。 Mauchly球形检验统计量W=0.800P=0.294不拒绝球形假设,各剂量间存在差异(F=11.358P=0.000),三个时间点间差异有显著性意义(F=27.565P=0.000),游离三碘甲状腺素中剂量与时间间存在交互作用(F=2.763P=0.02)。 Mauchly球形检验统计量W=0.982P=0.897不拒绝球形假设。各剂量间存在差异(F=7.010P=0.000),三个时间点间差异有显著性意义(F=6.629P=0.005),游离四碘甲腺原氨酸剂量与时间间不存在交互作用(F=0.689P=0.725)。 Mauchly球形检验统计量W=0.771P=0.23不拒绝球形假设。各剂量间存在差异(F=10.476P=0.000),三个时间点间差异有显著性意义(F=155.801P=0.000),剂量与时间间存在交互作用(F=22.235P=0.000),促甲状腺素中交互效应最明显的是14Gy照射后72小时。
结论
(1)：该研究表明18F-FDG-PET/CT的代谢程度能间接反映辐射剂量和组织损伤程度,这为PET/CT应用于急性放射病后的早期诊断提供了参考依据。
(2)：免疫器官是辐射高度敏感组织,全身照射后免疫器官(脾脏、胸腺及淋巴结)淋巴细胞在2、5、8、11Gy的死亡方式以凋亡为主。
(3)：甲状腺是辐射中度敏感组织,全身照射后甲状腺经历了照射后6小时功能亢进期,24小时活跃期及72小时功能低下期。
Background
With a large consume of nonrenewable resource. Nuclear is playing an important role in the process of industrialization, it offered the welfare for all aspects of our lives. However, the incidents, such as the atomic bombings of Hiroshima and Nagasaki, Three Mile Island accident, the Chernobyl Nuclear Accident and Fukushima Nuclear Accident have caused tremendous losses in the lives and properties of the people. Therefore, the researchers of all the world make a sustained effort for radiation protection, however, the management of radiation protection is remainly basis on the interaction between living tissue and ionizing radiation and the accurate measurement of doses. At present, the study are focus on the irradiated individual dosimetry in order to meet prompt, reasonable and effective medical treatment after a mass-casualty accidents. The traditional methods, such as peripheral blood lymphocyte counting, the dicentric chromosome assay, premature chromosome condensation and the micronucleus assay are very labor-intensive and time-consuming processes. However, some new methods, such as genetic techniques (Somatic mutations glycophorin A/hypoxanthine guanine phosphoribosyl transferase), gene expression assays and protein biomarkers (g-H2AX, C-reactive protein), being study. Therefore, it is very important to explore a new method that reflect the tissue damage and may be more simple, accurate, high-through.
Objective
The purpose of this study was mainly to investigate the damage rule of immune organ, kidney and thyroid gland and whether the PET/CT may be used to rapidly evaluate the damage after total irradiation
Materials and methods
All animal experimental protocols were in agreement with the guidelines established by the Institute and approved by the Institutional Review Board at the Southern Medical University Animal Care and Use Committee (License number SCXK (Yue)2006-0015). Adult uncastrated male Tibetan minipigs (weighing21.16±5.54kg, supplied by the Center for Laboratory Animals, Southern Medical University, Guangzhou, China) were maintained under standard laboratory conditions with a12-h light and12-h dark cycle; they were allowed free access to feed and water.
Forty-eight anesthetised (Sumianxin II:0.15mL/kg) Tibetan minipigs were divided into one control group and five experimental groups and placed in a phantom for fixation of postures to subject the animals to radiation exposure by an8-Mv X-ray (isocentric) linear accelerator (Precise System Treatment, ELEKTA, Sweden). The irradiation was carried out at the Cancer Centers of the Armed Police Hospital of Guangdong following the protocol described elsewhere. Animals in the experimental groups (n=9in each group) received a single-fraction total body irradiation (TBI) dose of2,5,8,11and14Gy, respectively. In the control group (n=3), the animals without received TBI. Physical dose within the chamber was assessed using direct-reading dosimeters (Arrow-Tech, Inc., Rolla, ND, USA). The dose rate was fixed as255cGy/min for all the treatment groups. The Tibetan minipigs were observed at three different time points (6,24and72h) after radiation exposure. Spleen, thymus and lymph node tissues and blood samples were also collected for histological examination(light and electron microscrope), apoptosis and blood analysis.
We chose the five radiation doses (namely,2,5,8,11and14Gy), each radiation dose has its own medical significance in humans. Radiation doses ranging from2to14Gy cause damage mainly to the haematopoietic system, the immune system and the gastrointestinal tract. In a scenario following a large nuclear event, different doses need different types of medical intervention. Subjects receiving below2Gy exposure cause no acute health effects and therefore need no supportive care. At approximately2-5Gy, these doses can be roughly doubled through the use of antibiotics, platelet and cytokine treatment. At a dose of approximately5-8or8-11Gy, bone-marrow transplantation is a useful option. There is usually lethal exposure above11Gy (14Gy) because of lethal gastrointestinal damage. Therefore, we believe that a dosimetry method that can rapidly and accurately distinguish doses ranging from2and11Gy is of utmost importance because people receiving these exposure doses all need immediate medical attention. We also select three observation time points (6,24and72h) post-irradiation, because the spleen responds rapidly and is very sensitive to TBI according to previous research (within hours post-irradiation). In addition, the latent period (from radiation exposure to symptom onset) is a critical time for medical intervention and the symptoms of ARS (acute radiation syndrome) can often appear within hours to weeks.
Positron-emission tomography, in combination with computed tomography using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG PET/CT), is a non-invasive diagnostic technique that utilises the biochemical metabolic differences between benign and malignant tissues; and it has achieved an established role in staging, restaging during treatment monitoring and prediction of response or non-response in many malignancies. However, varying degrees of18F-FDG uptake are found in normal tissues and in benign processes where F-FDG is used as a marker of glycolysis, moreover,18F-FDG does not specifically accumulate in malignancy. Previous studies have confirmed that18F-FDG evaluation can detect inflammatory and infectious processes that remain undetected during routine anatomical imaging. The study use this technique for research18F-FDG uptake difference in different tissue under physiology-pathological changes after different dose total body irradiation so as to deduce the relationship between tissue, dose and18F-FDG uptake.
Results
General condition:All the animals survived the irradiation procedures and were preserved during the observation period after exposure to total body irradiation. It caused loss of appetite, sluggish, erythema, weak in spirits and a decrease in activity of Tibetan minipig. However, with an increase in the radiation dose, the time to onset of vomiting and diarrhea appears earily, body surface area of erythema also become more large.
Counts of peripheral blood:the average WBC counts appeared to temporarily increase at6h post-irradiation, reach maximum value (12.98±0.23) at2Gy exposure; followed by a sharp decline with an increase in the radiation doses and prolongation of observation time points, reach minimum value (1.28±0.25) at72h after14Gy exposure. There were significant differences in the white blood cell (WBC) counts at24and72h after different dose exposure when tested using the one-way ANOVA test (A post hoc)(P<0.01). However, the average lymphocyte counts appeared to sharply decline with an increase in the radiation doses, reach minimum value at72h after14Gy exposure. There were significant differences in the lymphocyte counts at72h after different dose exposure when tested using the one-way ANOVA test (A post hoc)(P<0.01)..
Standard uptake value (SUV):Using the one-way ANOVA and repeated measures test, the mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.740P=0.665, there were significant different between irradiated groups (F=107.445, P=0.000) and between four time points (F=306.379, P=0.000), there were no significant different between control group and experimental group before TBI (F=0.375, P=0.856), there is interactive effect between dose and time points (F=32.894,P=0.000) and the significant effect was six hour after11Gy TBI.
Linear regression analysis to assess Spearman's correlation coefficient between spleen SUV and radiation dose at6,24and72h after TBI. The dose ddi not follow Gaussian distributions, and the correlation coefficient was r=0.94P<0.01,0.91P<0.01,0.82P<0.01, respectively. At6h post-irradiation, spleen SUV showed a clear and significant positive correlation with the radiation dose.
Splenic PET/CT imaging:The normal splenic uptake was generally of a low grade, in addition to being diffuse. with an increase in the radiation dose at6h post-irradiation, there was a gradual increase in18F-FDG uptake of the spleen. The18F-FDG uptake of the spleen increase with an increase in the radiation dose at24and72h but not obvious.
Standard uptake value (SUV) of both kidneys:the mauchly's test of sphericity was refused by hypothesis which Statistics was W=0.400P=0.081(left), W=0.387P=0.071(right), there were significant different between irradiated groups (left: F=225.289, P=0.000; right:F=114.942, P=0.000) and between four time points (left: F=195.210,P=0.000, right:F=188.081, P=0.000), there is interactive effect between dose and time points (left:F=44.008, P=0.000; right: F=42.223, P=0.000) and the significant effect was72hour after14Gy TBI. Both kidneys PET/CT imaging:The normal both kidneys uptake was generally of a low grade, in addition to being diffuse. With prolonging of observed time points in the14Gy group, the value of FDG uptake were increased more markly of bilateral renal parenchyma, which were also found at24and72hours in the11Gy group. But there were low FDG uptake in the2,5,8Gy and control group.
Light and electron microscope:Under the observation of light microscope, After2-14Gy radiation, the pathological changes of immune tissue (spleen, thymus and lymph node) lymphocytes underwent similar three pathological stages,the starting phase of death (apoptosis and necrosis) at6h post-irradiation, eliminating phase of debris at24h post-irradiation; exhausted phase of lymphocytes at72h post-irradiation. These changes were obvious at thymic cortex, splenic white pulp and germinal center of lymph nodes, the normal architecture of the lymph node is obliterated at24and72h after14Gy exposure.Under the observation of transmission electron microscope, RER and Golgi complex dilatation, nuclear swelling or pyknosis appeared in the lymphocyte of thymus, spleen and lymph node, nuclear condensation and fragmentation, chondriosome swell and ridge disappearance could be observed at6h after different dose total body irradiation, with an increase of radiation dose, lymphocyte apoptosis increase, phagocytic activity of macrophages also increase; the lymphocyte decrease at24h after different dose total body irradiation, the number of phagocytes become more and more, three to seven apoptotic lymphocyte or debris could be observed around phagocytes, with an increase of radiation dose, necrosis become more obvious, we could see spotty or lamellar necrosis area after14Gy exposure; apoptotic lymphocyte could not be observed at72h post-irradiation, with an increase of radiation dose, thymus, spleen and lymph node tissue become more lack, RER and chondriosome become more vacuolization. More animals showed no significant gross morphologic changes in the low dosage (2,5and8Gy) of the experiment. Areas of congestion and petechial hemorrhages were noted in the high dosage (11and14Gy). Definite abnormalities were present at24hours after high dosage under light microscopy, especially in the group receiving14Gy, there were acute congestion, inflammatory cells infiltration in renal interstitium, the formation of tube cast and the degeneration and necrosis of tubular cells, no obvious glomerular changes were noted except for congestion and endotheliocytic swelling of vessel. In contrast to the findings described above, under the electron microscope distinct changes were seen at6hours of11Gy. The obvious heterochromatin of the glomerular epithelial cells, endotheliocytic and focal fusion of foot processes were be seen. This became more marked with increase of observed time and dosage. The tubules manifested focal degenerative changes in the cytoplasm and nucleus as early as6hours after8Gy, consisting of the chromatin condensation and aggregation, dilatation of the agranular endoplasmic reticulum and the mitochondria, numerous lysosomal structures, and lipid droplets. This became more marked with increase of observed time and higher dosage.
After different dose irradiation, abundant lymphocyte apoptosis ratio was found in thymus,spleen and lymph node of Tibetan minipig. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.693P=0.133, there were significant different between irradiated groups (F=251.87, P=0.000) and between three time points (F=1530.24, P=0.000), there is interactive effect between dose and time points (F=145.36, P=0.000) and the significant effect of lymphocyte apoptosis ratio of spleen was six hour after14Gy TBI. The mauchly's test of sphericity was refused by hypothesis which Statistics was W=0.426, P=0.009, there were significant different between irradiated groups (F=1379.847,P=0.000) and between three time points (F=221.711,P=0.000), there is interactive effect between dose and time points (F=23.471, P=0.000) and the significant effect of lymphocyte apoptosis ratio of thymus was24hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.978P=0.883, there were significant different between irradiated groups (F=133.704,P=0.000) and between three time points (F=179.188,P=0.000), there is interactive effect between dose and time points (F=22.569,P=0.000) and the significant effect of lymphocyte apoptosis ratio of spleen was24hour after11Gy TBI.
The renal function testing include BUN and Cr. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.867P=0.456, there were significant different between irradiated groups (F=54.308,P=0.000) and between three time points (F=9.527,P=0.000), there is interactive effect between dose and time points (F=7.352, P=0.000) and the significant effect of BUN was24hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.840P=0.384, there were significant different between irradiated groups (F=54.308,P=0.000) and between three time points (F=104.753,P=0.000), there is interactive effect between dose and time points (F=20.842, P=0.000) and the significant effect of Cr was72hour after14Gy TBI.
The thyroid gland function testion include weight, FT3,FT4and TSH.The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.962P=0.808, there were significant different between irradiated groups (F=4.831,P=0.012) and between three time points (F=12.482,P=0.000), there is no interactive effect between dose and time points of weight (F=1.685, P=1.43). The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.800P=0.294, there were significant different between irradiated groups (F=11.358,P=0.000) and between three time points (F=27.565,P=0.000), there is interactive effect between dose and time points (F=2.763, P=0.02) and the significant effect of FT3was72hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.982P=0.897, there were significant different between irradiated groups (F=7.010,P=0.000) and between three time points (F=6.629,P=0.005), there is no interactive effect between dose and time points (F=0.689, P=0.725) of FT4. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.771P=0.23, there were significant different between irradiated groups (F=10.476, P=0.000) and between three time points (F=155.801,P=0.000), there is interactive effect between dose and time points (F=22.235, P=0.000) and the significant effect of TSH was72hour after14Gy TBI.
Conclusions
(1):This research showed that the metabolism of18F-FDG-PET/CT may indirectly reflect radiation dose and the extent of damage. This may provides reliable basis for PET/CT used to early diagnose to acute radiation disease.
(2):Immune organ is highly sensitive tissues for radiation. Apoptosis is the major death pathway of lymphocytes in2,5,8,11Gy treatment group.
(3):Thyroid gland is moderately sensitive tissues for radiation, it undergo hype-phase at six hours, active phase at24hours and hypo-phase after total body irradiation.
目前,核技术发展迅速,并已广泛应用于国民经济的各个领域。在核发电、农业育种、物理探矿、辐射加工和灭菌、疾病治疗、考古及科学研究等领域的应用,已取得了极大的经济效益和社会效益,促进了人类文明的进步。随着科学技术的不断发展,核技术应用的安全性也明显提高。但由于管理不善、违规操作规程等原因,发生核辐射事故并造成人员伤亡和环境污染的后果是灾难性的,如类似于苏联切尔诺贝利、美国三哩岛及日本福岛核泄露及日本广岛原子弹爆炸等。因此,全世界都在为辐射防护做出不懈的努力,而辐射防护的的管理依然是建立在电离辐射与活体组织之间相互作用(1)及特异的生物剂量测定法上。为了应对大规模辐射事故后伤员及时、合理及有效的救治,目前研究主要是集中在伤员所吸收的辐射剂量的测定。传统辐射剂量测定法(外周血淋巴细胞计数、双着丝粒染色体测定、染色体过早浓缩、微核)存在耗时、费力及非均一性等特点,而最新方法(遗传学技术(体细胞突变血型糖蛋白A、次黄嘌呤-鸟嘌呤磷酸核糖基转移酶)、基因表达测定法及蛋白标记物(g-H2AX及C反应蛋白))依然未得到统一的认可。因此,有必要探索更简单、准确、高通量且能全面反映组织损伤程度的新方法。
目的
这项研究主要是探讨全身辐射后免疫器官、肾脏和甲状腺的损伤规律及PET/CT可否对其损伤进行快速评估,为临床急性辐射病的诊断及救治提供实验依据。
材料及方法
这项研究得到了南方医科大学动物保护及使用委员会的批准(License number SCXK (Yue)2006-0015)。成年未阉割的西藏小型猪(体重21.16±5.54kg)由南方医科大学动物中心提供并在标准的实验室条件下圈养,它们可以自由摄入食物和水。
将48头已麻醉(Sumianxin Ⅱ:0.15mL/kg)的西藏小型猪按照辐射剂量随机分成一个对照组(0Gy)和五个实验组(2Gy,5Gy,8Gy,11Gy和14Gy),将麻醉后的实验组动物固定于放疗中心操作台上,接受8Mv X线(等中心的)线性加速器、辐射剂量率为255cGy/min的一次性全身辐射,所有的西藏小型猪在麻醉的条件下分别于各剂量全身照射前与照射后6、24和72小时接受18F-FDG-PET/CT检查,同时收集对照组及各剂量全身照射后6、24及72小时组西藏小型猪的免疫器官、肾脏及甲状腺等组织进行组织学检测(光镜和电镜)和流式细胞仪检测凋亡的淋巴细胞,同时也将收集的外周血进行分类计数、肾及甲状腺功能检测。
我们选择五个剂量组(2,5,8,11和14Gy),在人体这几个辐射剂量都有其自身的医学意义。辐射剂量从2到14Gy主要引起造血免疫系统及胃肠道系统的损伤。大规模急性辐射事故后,吸收不同辐射剂量的病人需要不同类型的医学干预和护理。接受2Gy以下的辐射一般不会引起急性效应因此不需要特别地支持治疗,在2-5Gy之间需要立即使用抗生素、血小板及细胞因子等综合治疗,在5-8Gy或者8-11Gy及时骨髓移植是挽救生命最佳的选择,而大于11Gy(14Gy)由于致命性的胃肠道的损伤目前是无法挽救的。我们选择2、5、8、11及14Gy这五个剂量组是因为能迅速且精确测定这些剂量有助于辐射伤员合理有效的救治。我们选择照射后6、24及72小时三个观察时间点是基于一方面潜伏期(辐射暴露到症状开始)对于医学干预是至关重要的,另一方面急性辐射综合症的症状一般在照射后几小时到几天内出现。
18F-FDG-PET/CT是一种根据良、恶性组织生物化学代谢差异的非侵袭性诊断技术,它广泛用于许多恶性肿瘤分期及分级并用于恶性肿瘤治疗后的检测。但是,作为葡萄糖类似物的18F-FDG在正常及良性组织中摄取也存在。此外,18F-FDG-PET/CT被证实也能检测炎症及感染过程。本实验利用该技术来研究不同剂量全身照射后各组织损伤后18F-FDG摄取的差异,以此来推断组织损伤、剂量及18F-FDG摄取三者之间的内在联系。
结果
一般观察：照射后72小时内各剂量组未见西藏小型猪死亡。照射后西藏小型猪精神状态不佳,食欲减退,懒怠,活动减少,皮肤红斑；随辐射剂量增加,呕吐和腹泻时间出现更早,皮肤红斑的面积也更大。
外周血细胞计数：不同剂量照射后,西藏小型猪外周血白细胞计数于照射后6小时出现短暂性升高,于2Gy达最大值(12.98±0.23)；随后迅速下降,于14Gy照射后72小时下降至最低值(1.28±0.25)。全身照射后外周血淋巴细胞数目迅速下降,于14Gy照射后72小时达最低值(0.065±0.029)。
脾脏标准摄取值(SUV)：采用单因素方差分析(one-way ANOVA)检验和一般线性模型(repeated measures)分析,Mauchly球形检验统计量W=0.740P=0.665不拒绝球形假设。各剂量间有显著性差异(F=107.445P=0.000),全身辐射前对照组与实验组间无显著性差异(F=0.375P=0.856),四个时间点间差异有显著性意义(F=306.379P=0.000),各时间点多重比较显示四个时间点间均有显著差异(P≤0.001)。剂量与时间点间存在交互作用(F=32.894P=0.000),11Gy照射后6小时交互效应最显著。用线性相关分析评估了不同剂量全身照射后6、24和72小时脾脏SUV值,其“辐射剂量”不服从正态分布,Spearman's相关系数分别是r=0.94P<0.01,0.91P<0.01,0.82P<0.01,且照射后6小时脾脏平均SUV与辐射剂量显示出清晰且显著的阳性相关。PET/CT影像学特征：正常脾脏18F-FDG摄取非常少且均一,照射后6小时脾脏18F-FDG吸收随剂量增加而显著增加,照射后24及72小时18F-FDG摄取也随剂量有所增加,但并不显著。
肾脏标准摄取值(SUV)：采用以上统计学分析,Mauchly球形检验统计量左侧：W=0.400P=0.081,右侧：W=0.387P=0.071,均拒绝球形假设。各照射剂量间存在显著性差异(左侧：F=225.289,P=0.000；右侧：F=114.942,P=0.000),四个时间点间差异有显著性意义(左侧：F=195.210,P-0.000；右侧：F=188.081,,P=0.000),各时间点多重比较四个时间点间无显著差异(P≥.05)。剂量与时间间存在交互作用(左侧：F=44.008.,P=0.000；右侧：F=42.223,P=0.000),交互效应最显著的均是14Gy照射后72小时。PET/CT影像学特征：对照,2,5及8Gy组18F-FDG的摄取非常少且均匀；而在11及14Gy组,随着观察时间的延长,双侧肾实质18F-FDG吸收值显著增高。
光镜及电镜：光镜下观察到不同剂量照射后胸腺、脾脏、淋巴结等免疫组织淋巴细胞损伤均出现基本相似的病理变化,经历了照射后6小时各组织淋巴细胞的死亡期(坏死与凋亡)、24小时淋巴细胞碎片的清除期及72小时淋巴细胞枯竭期三个病理发展阶段,这在胸腺皮质、脾脏白髓及淋巴结的生发中心表现最为突出。14Gy组24及72小时淋巴结切片见淋巴结结构遭到破坏。电镜下观察到照射后6小时见大量凋亡的淋巴细胞,核膜完整,染色质浓集,部分细胞的核碎片和胞浆成分形成凋亡小体,随照射剂量的增加,凋亡的淋巴细胞数量增多,吞噬现象也明显增多；24小时淋巴细胞数量明显减少,吞噬细胞数量显著增多,每个吞噬细胞中均可见到3-7个凋亡的淋巴细胞或细胞碎片,14Gy组淋巴结中见点状及片状坏死灶；72小时凋亡的淋巴细胞已难见到,随剂量增加,组织切片呈空虚状,网状细胞线粒体及内质网明显空泡化。光镜下观察到高剂量(11和14Gy)见局部淤血及出血,其明确的改变是在高剂量照射后24,72小时,尤其是接受14Gy照射组出现急性出血,肾间质炎症细胞的侵润,肾小管细胞的变性和坏死及管型的形成,肾小球仅见血管的充血及内皮细胞的肿胀；电镜下观察到显著的改变是11Gy照射后6小时,肾小球上皮细胞及血管内皮细胞异染色质明显增多；肾小管上皮细胞变性改变最早见于8Gy照射后6小时,异染色质凝集及聚集,线粒体及内质网扩张及大量溶酶体结构及脂滴。正常的甲状腺由大小均一的滤泡组成,其内充满均匀的胶质并由立方型滤泡上皮组成；全身照射后6小时,我们能观察到滤泡内充填浓的、深染的胶质及新形成的吸收空泡,其立方型滤泡上皮变成柱状型上皮；照射后24小时,甲状腺由大小不同的滤泡组成,其内充满薄的、淡然的胶质及混合型滤泡上皮；照射后72小时,甲状腺滤泡内少甚至无胶质充填,其周围由立方型上皮组成；三个时间点均能观察到间质不同程度血管充血、肿胀及炎症细胞的侵润(许多单核细胞及淋巴细胞),这些病理改变随剂量增加变得更严重。电镜下,正常组我们能观察到立方、柱状上皮细胞及显著的微绒毛,随着剂量的增加,微绒毛从正常到薄再到无,缝隙连接也逐渐变模糊,线粒体肿胀及内质网扩张,高剂量下我们能在核周围观察到异染色质聚集及浓缩。
不同剂量照射后脾脏、胸腺和淋巴结淋巴细胞的凋亡率情况。Mauchly球形检验统计量W=0.693P=0.133不拒绝球形假设,各剂量组间有显著性差异(F=251.87P=0.000),三个时间点间差异有显著性意义(F=530.24P=0.000,),剂量与时间间存在交互作用(F=145.36P=0.000),脾脏淋巴细胞凋亡率交互效应最显著是14Gy照射后6小时。Mauchly球形检验统计量W=0.426P=0.009,拒绝球形假设。各剂量间存在显著性差异(F=1379.847P=0.000),三个时间点间差异有显著性意义(F=221.711P=0.000),剂量与时间间存在交互作用(F=23.471P=0.000),胸腺淋巴细胞凋亡率交互效应最明显的是14Gy照射后24小时。Mauchly球形检验统计量W=0.978P=0.883不拒绝球形假设不拒绝球形假设,各剂量间存在显著性差异(F=133.704P=0.000)三个时间点间差异有显著性意义(F=179.188P=0.000),剂量与时间间存在交互作用(F=22.569P=0.000),淋巴结淋巴细胞凋亡率交互效应最明显的是11Gy照射后24小时。
肾功能测定主要包括肌酐及尿素氮：Mauchly球形检验统计量W=0.867P=0.456不拒绝球形假设,各剂量间存在显著性差异(F=54.308P=0.000),三个时间点间差异有显著性意义(F=9.527P=0.000),剂量与时间间存在交互作用(F=7.352P=0.000),交互作用最明显的是14Gy照射后24小时的尿素氮。Mauchly球形检验统计量W=0.840P=0.384不拒绝球形假设,各剂量间存在显著性差异(F=54.308P=0.000),三个时间点间差异有显著性意义(F=104.753P=0.000),剂量与时间间存在交互作用(F=20.842P=0.000),交互效应最明显的是14Gy照射后72小时的肌酐。
全身照射后甲状腺重量及功能的改变情况。Mauchly球形检验统计量W=0.962P=0.808不拒绝球形假设。各剂量间存在差异(F=4.831P=0.012),三个时间点间差异有显著性意义(F=12.482P=0.000),甲状腺重量中剂量与时间间不存在交互作用(F=1.685P=1.43)。 Mauchly球形检验统计量W=0.800P=0.294不拒绝球形假设,各剂量间存在差异(F=11.358P=0.000),三个时间点间差异有显著性意义(F=27.565P=0.000),游离三碘甲状腺素中剂量与时间间存在交互作用(F=2.763P=0.02)。 Mauchly球形检验统计量W=0.982P=0.897不拒绝球形假设。各剂量间存在差异(F=7.010P=0.000),三个时间点间差异有显著性意义(F=6.629P=0.005),游离四碘甲腺原氨酸剂量与时间间不存在交互作用(F=0.689P=0.725)。 Mauchly球形检验统计量W=0.771P=0.23不拒绝球形假设。各剂量间存在差异(F=10.476P=0.000),三个时间点间差异有显著性意义(F=155.801P=0.000),剂量与时间间存在交互作用(F=22.235P=0.000),促甲状腺素中交互效应最明显的是14Gy照射后72小时。
结论
(1)：该研究表明18F-FDG-PET/CT的代谢程度能间接反映辐射剂量和组织损伤程度,这为PET/CT应用于急性放射病后的早期诊断提供了参考依据。
(2)：免疫器官是辐射高度敏感组织,全身照射后免疫器官(脾脏、胸腺及淋巴结)淋巴细胞在2、5、8、11Gy的死亡方式以凋亡为主。
(3)：甲状腺是辐射中度敏感组织,全身照射后甲状腺经历了照射后6小时功能亢进期,24小时活跃期及72小时功能低下期。
Background
With a large consume of nonrenewable resource. Nuclear is playing an important role in the process of industrialization, it offered the welfare for all aspects of our lives. However, the incidents, such as the atomic bombings of Hiroshima and Nagasaki, Three Mile Island accident, the Chernobyl Nuclear Accident and Fukushima Nuclear Accident have caused tremendous losses in the lives and properties of the people. Therefore, the researchers of all the world make a sustained effort for radiation protection, however, the management of radiation protection is remainly basis on the interaction between living tissue and ionizing radiation and the accurate measurement of doses. At present, the study are focus on the irradiated individual dosimetry in order to meet prompt, reasonable and effective medical treatment after a mass-casualty accidents. The traditional methods, such as peripheral blood lymphocyte counting, the dicentric chromosome assay, premature chromosome condensation and the micronucleus assay are very labor-intensive and time-consuming processes. However, some new methods, such as genetic techniques (Somatic mutations glycophorin A/hypoxanthine guanine phosphoribosyl transferase), gene expression assays and protein biomarkers (g-H2AX, C-reactive protein), being study. Therefore, it is very important to explore a new method that reflect the tissue damage and may be more simple, accurate, high-through.
Objective
The purpose of this study was mainly to investigate the damage rule of immune organ, kidney and thyroid gland and whether the PET/CT may be used to rapidly evaluate the damage after total irradiation
Materials and methods
All animal experimental protocols were in agreement with the guidelines established by the Institute and approved by the Institutional Review Board at the Southern Medical University Animal Care and Use Committee (License number SCXK (Yue)2006-0015). Adult uncastrated male Tibetan minipigs (weighing21.16±5.54kg, supplied by the Center for Laboratory Animals, Southern Medical University, Guangzhou, China) were maintained under standard laboratory conditions with a12-h light and12-h dark cycle; they were allowed free access to feed and water.
Forty-eight anesthetised (Sumianxin II:0.15mL/kg) Tibetan minipigs were divided into one control group and five experimental groups and placed in a phantom for fixation of postures to subject the animals to radiation exposure by an8-Mv X-ray (isocentric) linear accelerator (Precise System Treatment, ELEKTA, Sweden). The irradiation was carried out at the Cancer Centers of the Armed Police Hospital of Guangdong following the protocol described elsewhere. Animals in the experimental groups (n=9in each group) received a single-fraction total body irradiation (TBI) dose of2,5,8,11and14Gy, respectively. In the control group (n=3), the animals without received TBI. Physical dose within the chamber was assessed using direct-reading dosimeters (Arrow-Tech, Inc., Rolla, ND, USA). The dose rate was fixed as255cGy/min for all the treatment groups. The Tibetan minipigs were observed at three different time points (6,24and72h) after radiation exposure. Spleen, thymus and lymph node tissues and blood samples were also collected for histological examination(light and electron microscrope), apoptosis and blood analysis.
We chose the five radiation doses (namely,2,5,8,11and14Gy), each radiation dose has its own medical significance in humans. Radiation doses ranging from2to14Gy cause damage mainly to the haematopoietic system, the immune system and the gastrointestinal tract. In a scenario following a large nuclear event, different doses need different types of medical intervention. Subjects receiving below2Gy exposure cause no acute health effects and therefore need no supportive care. At approximately2-5Gy, these doses can be roughly doubled through the use of antibiotics, platelet and cytokine treatment. At a dose of approximately5-8or8-11Gy, bone-marrow transplantation is a useful option. There is usually lethal exposure above11Gy (14Gy) because of lethal gastrointestinal damage. Therefore, we believe that a dosimetry method that can rapidly and accurately distinguish doses ranging from2and11Gy is of utmost importance because people receiving these exposure doses all need immediate medical attention. We also select three observation time points (6,24and72h) post-irradiation, because the spleen responds rapidly and is very sensitive to TBI according to previous research (within hours post-irradiation). In addition, the latent period (from radiation exposure to symptom onset) is a critical time for medical intervention and the symptoms of ARS (acute radiation syndrome) can often appear within hours to weeks.
Positron-emission tomography, in combination with computed tomography using 2-[18F]-fluoro-2-deoxy-D-glucose (18F-FDG PET/CT), is a non-invasive diagnostic technique that utilises the biochemical metabolic differences between benign and malignant tissues; and it has achieved an established role in staging, restaging during treatment monitoring and prediction of response or non-response in many malignancies. However, varying degrees of18F-FDG uptake are found in normal tissues and in benign processes where F-FDG is used as a marker of glycolysis, moreover,18F-FDG does not specifically accumulate in malignancy. Previous studies have confirmed that18F-FDG evaluation can detect inflammatory and infectious processes that remain undetected during routine anatomical imaging. The study use this technique for research18F-FDG uptake difference in different tissue under physiology-pathological changes after different dose total body irradiation so as to deduce the relationship between tissue, dose and18F-FDG uptake.
Results
General condition:All the animals survived the irradiation procedures and were preserved during the observation period after exposure to total body irradiation. It caused loss of appetite, sluggish, erythema, weak in spirits and a decrease in activity of Tibetan minipig. However, with an increase in the radiation dose, the time to onset of vomiting and diarrhea appears earily, body surface area of erythema also become more large.
Counts of peripheral blood:the average WBC counts appeared to temporarily increase at6h post-irradiation, reach maximum value (12.98±0.23) at2Gy exposure; followed by a sharp decline with an increase in the radiation doses and prolongation of observation time points, reach minimum value (1.28±0.25) at72h after14Gy exposure. There were significant differences in the white blood cell (WBC) counts at24and72h after different dose exposure when tested using the one-way ANOVA test (A post hoc)(P<0.01). However, the average lymphocyte counts appeared to sharply decline with an increase in the radiation doses, reach minimum value at72h after14Gy exposure. There were significant differences in the lymphocyte counts at72h after different dose exposure when tested using the one-way ANOVA test (A post hoc)(P<0.01)..
Standard uptake value (SUV):Using the one-way ANOVA and repeated measures test, the mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.740P=0.665, there were significant different between irradiated groups (F=107.445, P=0.000) and between four time points (F=306.379, P=0.000), there were no significant different between control group and experimental group before TBI (F=0.375, P=0.856), there is interactive effect between dose and time points (F=32.894,P=0.000) and the significant effect was six hour after11Gy TBI.
Linear regression analysis to assess Spearman's correlation coefficient between spleen SUV and radiation dose at6,24and72h after TBI. The dose ddi not follow Gaussian distributions, and the correlation coefficient was r=0.94P<0.01,0.91P<0.01,0.82P<0.01, respectively. At6h post-irradiation, spleen SUV showed a clear and significant positive correlation with the radiation dose.
Splenic PET/CT imaging:The normal splenic uptake was generally of a low grade, in addition to being diffuse. with an increase in the radiation dose at6h post-irradiation, there was a gradual increase in18F-FDG uptake of the spleen. The18F-FDG uptake of the spleen increase with an increase in the radiation dose at24and72h but not obvious.
Standard uptake value (SUV) of both kidneys:the mauchly's test of sphericity was refused by hypothesis which Statistics was W=0.400P=0.081(left), W=0.387P=0.071(right), there were significant different between irradiated groups (left: F=225.289, P=0.000; right:F=114.942, P=0.000) and between four time points (left: F=195.210,P=0.000, right:F=188.081, P=0.000), there is interactive effect between dose and time points (left:F=44.008, P=0.000; right: F=42.223, P=0.000) and the significant effect was72hour after14Gy TBI. Both kidneys PET/CT imaging:The normal both kidneys uptake was generally of a low grade, in addition to being diffuse. With prolonging of observed time points in the14Gy group, the value of FDG uptake were increased more markly of bilateral renal parenchyma, which were also found at24and72hours in the11Gy group. But there were low FDG uptake in the2,5,8Gy and control group.
Light and electron microscope:Under the observation of light microscope, After2-14Gy radiation, the pathological changes of immune tissue (spleen, thymus and lymph node) lymphocytes underwent similar three pathological stages,the starting phase of death (apoptosis and necrosis) at6h post-irradiation, eliminating phase of debris at24h post-irradiation; exhausted phase of lymphocytes at72h post-irradiation. These changes were obvious at thymic cortex, splenic white pulp and germinal center of lymph nodes, the normal architecture of the lymph node is obliterated at24and72h after14Gy exposure.Under the observation of transmission electron microscope, RER and Golgi complex dilatation, nuclear swelling or pyknosis appeared in the lymphocyte of thymus, spleen and lymph node, nuclear condensation and fragmentation, chondriosome swell and ridge disappearance could be observed at6h after different dose total body irradiation, with an increase of radiation dose, lymphocyte apoptosis increase, phagocytic activity of macrophages also increase; the lymphocyte decrease at24h after different dose total body irradiation, the number of phagocytes become more and more, three to seven apoptotic lymphocyte or debris could be observed around phagocytes, with an increase of radiation dose, necrosis become more obvious, we could see spotty or lamellar necrosis area after14Gy exposure; apoptotic lymphocyte could not be observed at72h post-irradiation, with an increase of radiation dose, thymus, spleen and lymph node tissue become more lack, RER and chondriosome become more vacuolization. More animals showed no significant gross morphologic changes in the low dosage (2,5and8Gy) of the experiment. Areas of congestion and petechial hemorrhages were noted in the high dosage (11and14Gy). Definite abnormalities were present at24hours after high dosage under light microscopy, especially in the group receiving14Gy, there were acute congestion, inflammatory cells infiltration in renal interstitium, the formation of tube cast and the degeneration and necrosis of tubular cells, no obvious glomerular changes were noted except for congestion and endotheliocytic swelling of vessel. In contrast to the findings described above, under the electron microscope distinct changes were seen at6hours of11Gy. The obvious heterochromatin of the glomerular epithelial cells, endotheliocytic and focal fusion of foot processes were be seen. This became more marked with increase of observed time and dosage. The tubules manifested focal degenerative changes in the cytoplasm and nucleus as early as6hours after8Gy, consisting of the chromatin condensation and aggregation, dilatation of the agranular endoplasmic reticulum and the mitochondria, numerous lysosomal structures, and lipid droplets. This became more marked with increase of observed time and higher dosage.
After different dose irradiation, abundant lymphocyte apoptosis ratio was found in thymus,spleen and lymph node of Tibetan minipig. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.693P=0.133, there were significant different between irradiated groups (F=251.87, P=0.000) and between three time points (F=1530.24, P=0.000), there is interactive effect between dose and time points (F=145.36, P=0.000) and the significant effect of lymphocyte apoptosis ratio of spleen was six hour after14Gy TBI. The mauchly's test of sphericity was refused by hypothesis which Statistics was W=0.426, P=0.009, there were significant different between irradiated groups (F=1379.847,P=0.000) and between three time points (F=221.711,P=0.000), there is interactive effect between dose and time points (F=23.471, P=0.000) and the significant effect of lymphocyte apoptosis ratio of thymus was24hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.978P=0.883, there were significant different between irradiated groups (F=133.704,P=0.000) and between three time points (F=179.188,P=0.000), there is interactive effect between dose and time points (F=22.569,P=0.000) and the significant effect of lymphocyte apoptosis ratio of spleen was24hour after11Gy TBI.
The renal function testing include BUN and Cr. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.867P=0.456, there were significant different between irradiated groups (F=54.308,P=0.000) and between three time points (F=9.527,P=0.000), there is interactive effect between dose and time points (F=7.352, P=0.000) and the significant effect of BUN was24hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.840P=0.384, there were significant different between irradiated groups (F=54.308,P=0.000) and between three time points (F=104.753,P=0.000), there is interactive effect between dose and time points (F=20.842, P=0.000) and the significant effect of Cr was72hour after14Gy TBI.
The thyroid gland function testion include weight, FT3,FT4and TSH.The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.962P=0.808, there were significant different between irradiated groups (F=4.831,P=0.012) and between three time points (F=12.482,P=0.000), there is no interactive effect between dose and time points of weight (F=1.685, P=1.43). The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.800P=0.294, there were significant different between irradiated groups (F=11.358,P=0.000) and between three time points (F=27.565,P=0.000), there is interactive effect between dose and time points (F=2.763, P=0.02) and the significant effect of FT3was72hour after14Gy TBI. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.982P=0.897, there were significant different between irradiated groups (F=7.010,P=0.000) and between three time points (F=6.629,P=0.005), there is no interactive effect between dose and time points (F=0.689, P=0.725) of FT4. The mauchly's test of sphericity was not refused by hypothesis which Statistics was W=0.771P=0.23, there were significant different between irradiated groups (F=10.476, P=0.000) and between three time points (F=155.801,P=0.000), there is interactive effect between dose and time points (F=22.235, P=0.000) and the significant effect of TSH was72hour after14Gy TBI.
Conclusions
(1):This research showed that the metabolism of18F-FDG-PET/CT may indirectly reflect radiation dose and the extent of damage. This may provides reliable basis for PET/CT used to early diagnose to acute radiation disease.
(2):Immune organ is highly sensitive tissues for radiation. Apoptosis is the major death pathway of lymphocytes in2,5,8,11Gy treatment group.
(3):Thyroid gland is moderately sensitive tissues for radiation, it undergo hype-phase at six hours, active phase at24hours and hypo-phase after total body irradiation.
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