西藏小型猪急性辐射损伤模型的建立及肠损伤机制的相关研究
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摘要
研究背景和目的
核恐怖、核污染及医源性核放射治疗对人类健康、安全及生存的影响非常广泛。尤其是近年来核事件如日本福岛核电站泄漏,朝鲜试验杀伤性核武器等引起了人们的广泛关注,如何在这种突发事件中做好应对是各国都非常关心的重点。大型核电站事故或核恐怖事件都会导致短时间内波及大量人员,受害者通常在短时间内受到高剂量辐射后产生全身反应,常伴有全身炎症,恶心呕吐,败血症,皮肤烧伤等症状。由于这些症状的特征不明显,再加上临床工作中,处理受到核辐射损害的患者非常罕见,大部分临床工作人员对这类受害者没有清楚的认识,不能正确及时的诊断病人的伤情并采取积极治疗措施。此外,全球每年有2000万肿瘤患者接受放射治疗,放疗后伴有辐射损伤症状的存活患者约150万。小肠组织的放射毒性仍然是腹部和盆腔肿瘤治疗的主要障碍,限制了高治疗剂量的使用。鉴于此,通过建立西藏小型猪急性辐射损伤模型来进行快速诊断方法和损伤机制的研究,可为临床辐射损伤的保护及救治提供新的思路。
[18F]-FDG-PET/CT(18氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法)是一种先进的分子成像诊断技术。其将先进的分子、功能、代谢成像与经典的解剖、形态、密度显示相互结合,不仅保留了经典解剖影像的作用,还加入了先进分子影像的功能,对于临床诊断具有重要的意义。目前,PET/CT在90%的临床应用主要用于早期发现或排除肿瘤、然而,关于[18F]-FDG-PET/CT在急性放射损伤中的应用报道较少。理论上,机体遭受不同程度的电离辐射后,全身发生炎症反应、甚者细胞凋亡、组织坏死,能量代谢通路会发生不同程度的改变,且这种改变必将导致[18F]-FDG的摄取发生变化。但辐照诱导的这种[18F]-FDG摄取的变化是否具有规律性?能否可用于快速诊断患者受照剂量并反映机体受损程度是本课题解决的问题之一。
PET/CT用于急性辐射病的诊断原理基于急性辐射病的发病机制与葡萄糖代谢异常紧密相关,而葡萄糖代谢是机体能量代谢的重要组成部分。线粒体是小肠能量代谢的结构基础,是细胞有氧氧化合成ATP的部位,同时也是对辐射损伤最敏感的细胞器之一。我们通过对小肠线粒体复合物酶活,呼吸功能,能量物质的含量及荧光定量PCR测定线粒体蛋白编码基因的表达,展示了辐射引起小肠线粒体各指标的变化和相互关系,为能量代谢通路障碍的分子机制提出了进一步的验证。
方法
第一章西藏小型猪急性辐射病模型的建立
选用未去势雄性西藏小型猪为动物模型(n=54),实验组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/min。对照组9只未予照射。观察西藏小型猪辐射后呕吐、腹泻,大便隐血、外周血淋巴细胞计数及淋巴结淋巴细胞凋亡等指标,分别于照射后6、24、72小时予西藏小型猪分别处死实验组中的三只小型猪,光镜及电镜观察不同剂量不同时间点下西藏小型猪小肠及淋巴结的形态学变化。根据临床现有的辐射病分级标准,比较不同剂量辐射后小型猪的症状与人类急性放射病模型的特点,确定西藏小型猪急性辐射病模型的成功建立。数据分析采用析因法对外周血淋巴细胞计数,淋巴结淋巴细胞凋亡率进行分析。如剂量、时间因素的交互效应及主效应p值小于0.05,则应分别固定时间因素及剂量因素,并用单因素方差分析法对两者的简单效应进行分析。组内多重比较根据方差齐性结果,分别用最小差值法(LSD)或Games-Howell法进行分析。小肠病理评分结果主要采用K-INDEPENDENT Samples非参数检验法进行检测。所有数据处理均用Statistical Product and Service Solutions13.0(SPSS13.0)软件完成。
第二章PET/CT在急性辐射病中的应用探索
实验动物分组及辐照条件参照第一章,PET/CT扫描方法如下：麻醉后,西藏小型猪静脉注射造影剂一小时后开始扫描。扫描所获图像及数据均通过Xeleris工作站系统进行处理。对FDG摄取的定量主要通过：1)划定目的区域(regions of interest, ROIs),本章目的脏器为小肠。2)通过Xeleris工作站系统自动计算注入的FDG剂量与ROIs之间的比值(%ID)。数据的标准化均由电脑自动完成并以SUV值的形式输出。为使图像更为直观的表现出SUV值的差距,本研究主要应用rainbow伪彩模式并将所生成图片的颜色参照彩图条进行设定。为保证结果的客观真实性,我们做了下列措施：1)注入FDG的量统一以0.11-0.13millicurie/kg/猪进行计算；2)所有的实验用猪在进行PET/CT扫描前,至少禁食8小时保证血糖水平的均一和稳定；3)同时对三个相邻层面的SUV最大值进行扫描收集并用以统计学分析；4)小型猪统一于FDG注射后1小时进行扫描。统计方法如下：数据均以均数±标准差的形式进行表示。用析因分析法对小肠SUV值进行分析。如剂量、时间因素的交互效应及主效应p值小于0.05,则应分别固定时间因素及剂量因素,并用单因素方差分析法对两者的简单效应进行分析。组内多重比较根据方差齐性结果,分别用最小差值法(LSD)或Games-Howell法进行分析。P值小于0.05被视为具有统计学差异(双尾)。
第三章急性辐射病的能量代谢损伤机制
本实验所用的18只成年雄性西藏小型猪来自第一章动物分组中2,5,8,11,14Gy的72小时组及对照组。对照组3只,实验组每组3只,静脉注射速眠新麻醉(0.05ml/kg)后分别接收2,5,8,11,14Gy单次X线照射。于辐射72小时麻醉处死前,进行各项能量代谢指标的测定。能量代谢的观察指标包括线粒体超微结构观察、线粒体呼吸链酶复合物活力的测定、线粒体呼吸功能的测定、高效液相色谱法测定不同类型辐射病小肠腺苷酸含量、不同类型急性辐射病蛋白质编码基因的测定。统计方法均采用单因素方差分析。单位湿重能量物质与单位DNA能量物质与病理积分的相关性采用Spearman法,统计软件为SPSS13.0。
结果
第一章西藏小型猪急性辐射病模型的建立
西藏小型猪在辐射后24小时,72小时的腹泻,呕吐及大便隐血评分均无统计学差异(P值>0.05)。各时间点外周血淋巴细胞计数均随着辐照剂量的增加而降低。与对照组相比,各剂量组之间的差异在72h组最为明显。从形态学来看,各实验组随着剂量的增加,淋巴结的体积缩小,出血明显,淋巴细胞数明显下降。西藏小型猪各剂量组辐射6h淋巴结内每个淋巴小结区域的淋巴细胞数目与对照组无明显差异,但在24h和72h,淋巴结内淋巴细胞的数目随着剂量的升高明显降低,且显示出剂量效应。淋巴结淋巴细胞的凋亡率在各时间点都与对照组有统计学差异(P<0.05),2Gy-11Gy之间随着辐射剂量上升,凋亡率也明显上升。72h时,细胞凋亡率在8Gy-14Gy区间内无统计学差异。除了11Gy,同一剂量6h、24h和72h的凋亡率相比,没有统计学差异。各时间点,11Gy组的凋亡率是最高的。辐射后,分别于6小时,24小时和72小时处死不同剂量组的3只西藏小型猪,肉眼观察到不同剂量组各时间点小肠组织变化没有明显差异。照射后6小时即能观察到小肠组织的损伤,但总体来说72小时病变更为明显直接。2Gy组和对照组的小肠组织没有明显不同,5Gy组观察到小肠黏膜面基本平滑,绒毛和皱襞消失,肠壁变薄,小血管扩张、水肿和充血、出血、血淤滞、微血栓、有散在小片状或点状出血。8Gy及11Gy出血多呈斑点状,发生广泛或弥漫性出血,有1只动物观察到肠道大量出血性积聚和血凝块。14Gy组所有动物都出现肠黏膜面大范围的弥漫性出血或肠腔内积血,绒毛上皮发生广泛坏死,黏膜枯萎,肠绒毛裸露。病理结果的半定量积分评估分析,发现病理积分随着剂量的增加明显增加,剂量效应大于时间效应。电镜观察淋巴结细胞的超微结构在11Gy之前组均显示典型的凋亡细胞形态结构。例如,浓缩的染色质及早期染色质边缘集中,中期典型的新月体和环状染色质,细胞质细胞器紧贴,晚期细胞皱缩及凋亡小体。电镜下可见其变化主要表现为细胞核异常(核固缩；核破裂、核溶解等改变,异染色质边缘化,异染色质增多或减少)、小肠绒毛缺失。且变化程度均随放射剂量的增加而增加。11-14Gy的形态学结果显示除了凋亡,组织主要显示出坏死的典型特征。
第二章PET/CT在急性辐射病中的应用探索
照射剂量因素及观察时间点因素对小肠FDG摄取的影响具有显著性。剂量因素、时间因素及两者的交互效应p值均小于0.05)固定时间因素可知：放射后6小时,2Gy组(1.15±0.16)、5Gy组(1.36±0.18)SUV值相较于对照组(1.16±0.26)无统计学差异(2、5Gy组vs对照组,p值均>0.05),8Gy组(2.56±0.38)、11Gy组(2.81±0.28)、14Gy组(1.47±0.31)SUV值均高于对照组(1.16±0.26)有统计学差异,11Gy时达到最高点。
放射后24小时,2Gy组(1。19±0.15)、5Gy组(2.25±0.16)、8Gy组(4.25±0.32)SUV值较对照组是依次升高的趋势(5、8Gy组vs对照组,p值均小于0.05),这个时间点SUV值的最高点出现在8Gy,11Gy组(2.20±0.12)开始低于8Gy、14Gy组(0.76±0.14)SUV值更下降到低于对照组(11Gy组、14Gy组vs对照组p值均小于0.05)。各剂量组之间比较有统计学差异(2Gy组vs5Gy组、5Gy组vs8Gy组、8Gy组vs11Gy组,所有p值均小于0.01),但11Gy组及14Gy组间并无统计学差异(11Gy组vs14Gy组,p值大于0.05)；总体来说24h时间点,SUV值的最高点出现在8Gy,低于8Gy时SUV值随剂量的增加而升高,高于8Gy随着剂量的升高而降低。
放射后72小时,2Gy组(1.84±0.24)、5Gy组(2.93±0.43)SUV值较对照组(1.16±0.10)明显升高(2、5Gy组vs对照组,p值均<0.05),8Gy组(7.03±0.91)、11Gy组(4.09±0.43)SUV值高于对照组且有统计学差异,反之,14Gy组(0.42±0.09)SUV值明显低于对照组(11、14Gy组vs对照组,p值均<0.05),但11、14Gy组SUV值无统计学差异(11Gy vs.14Gy, p>0.05).固定剂量因素可知：放射剂量为2、5、8Gy时,FDG摄取在放射后24及72小时均高于放射后6小时。其变化趋势为放射后24小时FDG摄取>72小时>6小时。放射剂量为11、14Gy时,FDG摄取随观察时间的延长而进行性降低。
第三章急性辐射病的能量代谢损伤
电镜下放射后72小时小肠超微结构进行观察,其变化主要表现为细胞核异常(核固缩；异染色质边缘化；异染色质增多或减少)、线粒体扩张及空泡化。酶活结果表明,复合酶物Ⅰ,Ⅱ,Ⅲ,Ⅳ辐射后72小时的趋势大致相同。复合物酶Ⅰ各实验组与对照组均有显著性差异(P值<0.05),在2-8Gy酶活性明显降低,2Gy,5Gy,8Gy组之间有显著性差异(P值<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅱ2Gy与对照组无显著性差异,2G,5Gy,8Gy组之间有显著性差异(P值<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅲ2Gy与对照组有显著性差异(P值<0.05),其余组与对照组的显著性P值<0.01,2Gy与5Gy之间的差异P值小于0.01,5Gy和8Gy组之间有显著性差异(P<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅳ的变化与复合酶Ⅱ相似,低剂量辐射时,无显著性变化,从5Gy开始有明显下降,最明显的变化出现在2-5Gy之间(P<0.01)。与对照组比较,实验组两条呼吸链R3、P/0及RCR均随着剂量的增加显著降低,R4随着剂量增加而增加,说明辐射导致小型猪小肠线粒体呼吸功能下降,氧化磷酸化偶联作用松弛。8Gy以下,各组组间变化明显,超过8Gy之后,呼吸功能无明显变化。不同放射剂量X线辐射后72小时小肠ATP、ADP、AMP和TAN含量(nmol/g湿重)均有显著变化且变化各具特点。(p值均小于0.01)我们发现ATP、ADP和TAN含量在2Gy到8Gy之间随着辐射剂量的增加而降低,显示出剂量效应,而8Gy之后各组腺苷酸含量之间的无统计差异。小肠线粒体能量物质与DNA的比值与单位湿重能量物质的含量趋势一致,表明能量代谢是细胞损伤的机制之一。单位湿重小肠能量物质含量与单位DNA能量物质含量与病理积分的相关性比单位湿重能量物质的变化和病理改变更加紧密。各能量物质中,TAN含量的改变和病理变化相关性最高。RT-PCR结果表明,与线粒体相关的13个基因在辐射后72小时的趋势大致相同。各实验组的表达量均与对照组显著差异,低于8Gy,各剂量组之间显著性差异,各基因的表达量明显大幅度降低,显示出剂量效应。8Gy组的表达量仅为正常组的20%左右,而高于8Gy的实验组之间无显著性差异。
结论：
第一章西藏小型猪急性辐射病模型的建立
1、我们在2Gy-14Gy的辐射区间内成功复制出西藏小型猪不同剂量的急性辐射病模型,小型猪辐射后外周血淋巴细胞计数、细胞凋亡率、病理变化和人类急性辐射病症状非常相似,可以作为急性辐射病的动物模型。
2、根据病理和超显微结构的观察,西藏小型猪不同剂量的急性辐射病的损伤机制存在不同,有待进一步的探索。
第二章PET/CT在急性辐射病中的应用探索
1、不同时间点,PET/CT检测不同剂量组西藏小型猪急性辐射病模型,SUV值的趋势相同,均为先上升,再下降。拐点位置在8Gy。结合患者的临床症状,SUV值可作为急性辐射病诊断和预后的参考。
2、低剂量辐射后SUV值升高可能由于机体的炎症反应导致,高剂量辐射后SUV值降低主要原因为机体遭到极大损伤,组织结构破坏严重,出现坏死,生物体能量代谢障碍。
第三章急性辐射病的能量代谢损伤
辐射导致小肠线粒体能量生成障碍的发生是多环节、多组分共同作用的结果,辐射剂量低时,能量代谢仍能维持一定水平时,但没有完全失衡,细胞功能仍有恢复的可能；当能量物质下降到一定程度时,恢复的几率大大降低。呼吸链复合物酶活性的降低、氧化与磷酸化脱偶联加强、呼吸功能降低,mt DNA的损伤以及能量物质的改变等,均起一定的作用,这些组分均可能成为提高辐射后线粒体能量生成效率的有效干预靶点。
Purpose and background:
The influence of nuclear terrorism, nuclear contamination and nuclear radiation therapy to human survival,safety and health has become a hot topic of current medical research. Large-scale nuclear accident or nuclear terrorist incident may result in a large number of casualties in a short time. The victims radiated by high-dose in a short time are often accompanied by symptoms of systemic reaction, such as systemic, inflammation, nausea, vomiting, septicemia, and skin burns. Due to there is no obvious features of these symptoms, coupled with the clinical work by the personnel nuclear radiation damage is not very common, when in the situation of dealing with such a victim, most of clinical staff dose not have a clear understanding on how to diagnosis the patient's injury and take what kind of active treatment measures. In addition, there are still over200,000cancer patients undergoing radiotherapy all over the world annually, even more than about1.5million of the survival of patients with symptoms of intestinal radiation damage after radiotherapy. Small intestinal tissue radiation toxicity remains a major obstacle to the treatment of abdominal and pelvic tumors, limiting the use of high therapeutic doses. In view of this, a detailed understanding of the intestinal tract to ionizing radiation damage mechanisms and diagnostic methods is very necessary to help taking the effective means to reduce the intestinal damage caused by the clinical course of treatment and improve quality of life in patients.
18-fluoro glucose positron emission tomography/computed tomography X-ray photographic method.(([18F]-FDG-PET/CT) is an advanced molecular imaging diagnostic techniques. This machine combines molecular mechanism,functional analysis, metabolic imaging with classic anatomy, shape, density not only retains the classic role of the anatomical images, and also joined the functionality of advanced molecular imaging, is of great significance for clinical diagnosis. At present, oncology diagnosis in its clinical applications occupied more than90%in this field, mainly used for early detection or exclusion of tumor. However, However, whether [18F]-FDG-PET/CT can be useful in the diagnosis in acute radiation injury is rarely reported. In theory, when the body expose to varying degrees of ionizing radiation, systemic inflammatory response may occur and energy metabolism pathways would be change to some extent, thus will inevitably lead to the change of [18F]-FDG uptake. But is this changes in[18F]-FDG uptake in TBI-induced radiation damage with regularity? Can it be used for rapid diagnosis of exposure doses and reflect the extent of the damage of the body? Which is one of the subject to solve the problem.
The principle on PET/CT for the diagnosis of acute radiation sickness is closely related to the pathogenesis of acute radiation sickness and energy metabolism abnormalities. Mitochondria are the structural basis of the small intestine energy metabolism, the most important part of cell aerobic oxidation in the process for the synthesis of ATP, and also the most radiation sensitive organelles. Through the measurement of small intestine mitochondrial complex activity, respiratory function, the contents of the energy substances and the quantitative PCR determination of expression of the mitochondrial protein coding, gene, we plan to show a radiation-induced changes in indicators of the small intestine, on the basis of the above assumption we can also bring out some hypothesis of the possible molecular mechanism of energy metabolism damage further.
Methods:
Chapter one:The establishment of Tibet mini pig model
The establishment of acute radiation disease model of Tibet mini-pigs. Not castrated male Tibetan mini pig was chose as an animal model (n=54), the radiation groups were exposed to the of2,5,8,11,14Gy of single dose of irradiation (n=9/group) with a linear accelerator, the dose rate was255cGy/min.9of the control group were not irradiated. We recorded vomiting, diarrhea, fecal occult blood, peripheral blood lymphocyte count and lymph node lymphocyte apoptosis index of Tibet mini pigs. Three Tibet mini pigs of the experimental group were sacrificed at6,24,72hours after irradiation respectively, we ovserved the morphological changes of small intestine and lymph nodes by light and electron microscope at different time points. Based on the existing clinical grading standards of acute radiation disease, we classified the symptoms of mini pigs in the different doses of radiation corresponds to a different classification of human acute radiation sickness model, and determine the successful establishment of the
Tibet mini pigs of acute radiation disease model.
The data of peripheral blood lymphocyte count, lymph node and lymphocyte apoptosis were analyzed by repeated measure variance analysis. When interaction effects of factors such as dose, time and the main effect of p-value were less than0.05, variance such as time factors, dose factors or the simple effect of both single-factor should be fixed to analysis.According to multiple comparisons of the homogeneity of variance results within the groups,the minimum difference method (LSD) or Games-Howell method was used for further analysis. K-INDEPENDENT the samples of non-parametric test was applied in intestinal pathological findings. All the data have to deal with are using the Statistical the Product and Service Solutions13.0(SPSS13.0) software.
ChapterⅡ The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
Experimental animal group and the irradiation conditions were the same as the chapter one mentioned. PET/CT scanning methods as follows:After anesthesia, PET/CT begin scanning one hour after intravenous contrast agent to mini pigs. Images and data obtained from scanning further processed through Xeleris work station system. Quantitative FDG uptake mainly through:1, Deline the regions of interest (regions of interest, ROIs), this chapter is mainly for the small intestine.2, Xeleris workstation system can automatically calculates the ratio (%ID) of the injected dose between regions of interest.Standardization and correction of data was automatically performed by computer and output in the form of SUV values..In order to make the image more vividly present the gap between different SUV values,we set up rainbow pseudo-color mode and transferred the PET/CT image into color reference according to the color pictures bar. To ensure the objectiveness and authenticity of results, following measures had been done:1) the amount of FDG injected into Tibet mini pig is0.11-0.13millicurie/kg/pig,2) In order to control blood sugar levels all experimental pigs at least faste eight hours before the PET/CT scan,3) We recorded maximum SUV value of three adjacent scanning levels for further statistical analysis.4) All mini pigs are scanned one hour after the injection of FDG. Statistical methods are as follows:The data are presented as mean±standard deviation. SUV value were analyzed by repeated measure variance analysis. When interaction effects of factors such as dose, time and the main effect of p-value were less than0.05, variance such as time factors, dose factors or the simple effect of both single-factor should be fixed to analysis.
According to multiple comparisons of the homogeneity of variance results within the groups,the minimum difference method (LSD) or Games-Howell method was used for further analysis. P values less than0.05was considered statistically significant (two-tailed). The small intestine SUV and pathological damage degree of correlation analysis using Spearman method.
Chapter III Injury mechanisms of energy metabolism in acute radiation sickness
18adult male Tibet mini pigs used in this experiment came from the72hours subgroup in groups of2,5,8,11,14Gy and control group which were used in chapter one. The experimental group were3pigs while the control one is the same.72hours after radiation pigs were sacrificed, we determine the related energy metabolism indicators. The energy metabolism indicators includes the observations of mitochondrial ultrastructural, the mitochondrial respiratory chain enzyme complex activity,mitochondrial respiratory function,adenylate content of the small intestine by high performance liquid chromatography (HPLC) method,the copies of protein-coding genes.
Results
Chapter I:The establishment of Tibet mini pig model
24hours and72hours after radiation, the data of diarrhea, vomiting and fecal occult blood score Tibet mini pig were not statistically different (P>0.05). At all time points in peripheral blood lymphocyte counts were reduced with increasing radiation dose. Compared with the control group, the differences between each dose group is most obvious in the72h group. Overall, in all experimental groups with increasing dose, lymph nodes became smaller in size, bleeding was more severe, the lymphocyte count decreased significantly. The number of lymphocytes ineach lymphoid nodule area in the Tibet mini pig6h after radiation has no significant difference. At24h and72h, the number of
lymphocytes in lymph nodes decreased significantly with the increasing dose, and showed a dose-response. Lymphocytes apoptosis rate in lymph node and the control group at each time point has significant difference (P<0.05), with the increase in radiation dose between the2Gy-11Gy, the apoptosis rate increase signicicantly. At72h, the apoptosis rate has no significant different between the range of8Gy-14Gy. Except for11Gy, the same dose at6h,24h and72h, the apoptosis rate has no statistical significance. At each time point, the apoptosis rate of11Gy group is the highest,6hours,24hours and72hours after radiation, three Tibet mini pigs from different dose groups were sacrificed respectively, there is no significantly difference in different time point of the same dose in visual observation of the intestinal tissue.
visual observation to the intestinal tissue changes of the different dose groups at each time point has no significant difference., We can observe small intestinal tissue injury as early as6hours after irradiation, however, on the whole, lesions in72hours was more obvious and direct. Intestinal tissue of2Gy group and control group was not significantly different. We found that the small intestine mucosa surface was basically smooth in5Gy group,but we can also found the villi became sparse and short, the small vascular expanded and there was dot like bleeding.8Gy and11Gy bleeding became more severe and found blood blot extensively. In14Gy group, all animal showed extensive bleeding, blood blot and diffuse hemorrhage in the mucosal surface of intestine, chorioepithelium appeared extensive necrosis, hardly no villi can be saw and intestinal villi hardly gone. The semi-quantity score of pathology showed an increase trend with dose increase, and the dose effect was more obvious than time effect. The ultrastructure of intestine and lymph note showed typical apoptosis cell state before dose of11Gy, we can see the typical apoptosis cell indicators such as concentrated and edging of chromatin at early phase, Crescent and ring chromatin at the media phase and apoptotic bodies at the late phase. While at14Gy the ultrastructure showed typical necrosis in the both organs.
ChapterⅡ The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
Factors such as radiation dose and observation time both have significant influence on FDG uptake of intestine. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, small-intestinal FDG uptake in2and5Gy showed no difference from control group, while those in8,11and14Gy were higher than control group. At24h post-TBI, small-intestinal FDG uptake showed no difference between2Gy-group and control group. Those in5,8and11Gy-group were higher than control group, while those in14Gy-group was lower than control group. It should be noted that on the time-points of6and24h post-TBI, FDG uptake in2,5and8Gy increased with the increase of radiation doses, while the reverse trend were shown in the following doses. At72h post-TBI, small-intestinal FDG uptake showed a radiation dose-dependent increase in the dose range of2to8Gy, while the rapid and marked decreases were shown in11and14Gy-group. To the simple effect of time-points, small-intestinal FDG uptake increased with the time prolonging in2,5and8Gy-group, while the reversed trend was shown in11and14Gy-group.
Chapter III Injury mechanisms of energy metabolism in acute radiation sickness
The main morphology of intestine under TEM was the abnormal of nuclear.(the condensed nucleus, the edging of heterochromatin, increased or reduced heterochromatin),the expand and vacuolization of mitochondria. The results of enzyme complexes activities showed, enzyme complex Ⅰ,Ⅱ,Ⅲ and IV at72h after radiation almost the same trend. The complex I in all experiment group has significant difference with the control group.(P<0.05), its activity decreased sharply at2-9Gy and there are significant differences between dose group2-8Gy, while from8-14Gy there was no significant different among them. Complex II has no significant difference between2Gy group and control group, however, there were significant difference in the range of2-8Gy,the later dose group show the same trend with complex I.The P value of complex III in2Gy and control is less than0.05,while the other group was0.01. The change of complex IV was almost the same as complex II, which didn't change until5Gy, then there is a sudden drop from5Gy.
Compared with control group, the value of R3,P/O, and RCR is decreasing with increase dose, which means the dysfunction of mitochondrial respiratory chain and relaxation of oxidative Phosphorylation.8Gy is the key point, that prior to 8Gy the following change is evident, while no significant changes in respiratory function when the dose is more than8Gy.72hours after X-ray radiation, the ATP, the ADP, AMP, and TAN content (nmol/gwet weight) of different doses of radiation in small intestine are significantly changing and has its own change characteristics respectively.(P-value is less than0.01). We found that ATP, ADP, and TAN content decreases with increasing radiation dose in2Gy to8Gy, showing a dose effect, but after8Gy, no statistical difference between the group of adenylate content. The ratio of mitochondrial energy substances and DNA in small intestine and energy substances trends, indicating that energy metabolism is one of the mechanisms of cell injury. Compared with the energy of the unit wet weight of the small intestine material content, the relationship of unit DNA-energy matter content with pathological integral unit wet weight of energy material changes and pathological changes was more closely. Of all energy materials, the changes of TAN content has the closest relationship with pathological changes. RT-PCR results showed that the trend of the13genes associated with mitochondria encoding protein in the72hours after irradiation were almost the same. Significant differences existed in expression levels for each experimental group and control group less than8Gy, there are significant differences between each dose group, the amount of gene expression is obviously reduced, showing a dose effect. The expression of8Gy group only about20%of the normal group, but higher than8Gy, there is no significant difference among the experimental group.
Conclusions:
Chapter I:The establishment of Tibet mini pig model
1、We successfully established different stages of acute radiation sickness in Tibet mini pig model at range of2Gy-14Gy radiation
2、Based on pathology and ultrastructure observation, there is different injury mechanism in Tibet mini pig at different stages of acute radiation sickness, we need to further explore.
Chapter Ⅱ:The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
1、At different time points, we use PET/CT to detect the different dose groups in Tibet mini pigs with acute radiation sickness model, the same trend of SUV values were first increased and then decreased. Inflection point location is about5Gy to8Gy. It proves that PET/CTdoes not apply to the determination of the radiation dose acute radiation sickness.
2、We speculated that in the case of the presence of inflammation, the reason that the SUV value even decrease may be the possibility of reduced glucose metabolism due to obstacle in organism energy metabolism is much greater than the increased glucose metabolism trigered by inflammation.
Chapter Ⅲ Injury mechanisms of energy metabolism in acute radiation sickness
Radiation-induced intestinal mitochondrial energy generation obstacle is the result of multi-link, multi-component. If the radiation dose is not lethal, energy metabolism can still maintain a certain level, but not completely off balance, cell function may recover. When the energy of the material drop to a certain extent, the chance of recovery is greatly reduced. The decrease of respiratory chain complex activity, the strengthen uncoupling of oxidative phosphorylation,the reduction of respiratory function and mtDNA damage as well as the energy changes of substance, all play a role in mitochondrial energy production, which to improve to be an effective intervention target.
核恐怖、核污染及医源性核放射治疗对人类健康、安全及生存的影响非常广泛。尤其是近年来核事件如日本福岛核电站泄漏,朝鲜试验杀伤性核武器等引起了人们的广泛关注,如何在这种突发事件中做好应对是各国都非常关心的重点。大型核电站事故或核恐怖事件都会导致短时间内波及大量人员,受害者通常在短时间内受到高剂量辐射后产生全身反应,常伴有全身炎症,恶心呕吐,败血症,皮肤烧伤等症状。由于这些症状的特征不明显,再加上临床工作中,处理受到核辐射损害的患者非常罕见,大部分临床工作人员对这类受害者没有清楚的认识,不能正确及时的诊断病人的伤情并采取积极治疗措施。此外,全球每年有2000万肿瘤患者接受放射治疗,放疗后伴有辐射损伤症状的存活患者约150万。小肠组织的放射毒性仍然是腹部和盆腔肿瘤治疗的主要障碍,限制了高治疗剂量的使用。鉴于此,通过建立西藏小型猪急性辐射损伤模型来进行快速诊断方法和损伤机制的研究,可为临床辐射损伤的保护及救治提供新的思路。
[18F]-FDG-PET/CT(18氟代葡萄糖正电子发射断层扫描术/计算机层析X射线摄影法)是一种先进的分子成像诊断技术。其将先进的分子、功能、代谢成像与经典的解剖、形态、密度显示相互结合,不仅保留了经典解剖影像的作用,还加入了先进分子影像的功能,对于临床诊断具有重要的意义。目前,PET/CT在90%的临床应用主要用于早期发现或排除肿瘤、然而,关于[18F]-FDG-PET/CT在急性放射损伤中的应用报道较少。理论上,机体遭受不同程度的电离辐射后,全身发生炎症反应、甚者细胞凋亡、组织坏死,能量代谢通路会发生不同程度的改变,且这种改变必将导致[18F]-FDG的摄取发生变化。但辐照诱导的这种[18F]-FDG摄取的变化是否具有规律性?能否可用于快速诊断患者受照剂量并反映机体受损程度是本课题解决的问题之一。
PET/CT用于急性辐射病的诊断原理基于急性辐射病的发病机制与葡萄糖代谢异常紧密相关,而葡萄糖代谢是机体能量代谢的重要组成部分。线粒体是小肠能量代谢的结构基础,是细胞有氧氧化合成ATP的部位,同时也是对辐射损伤最敏感的细胞器之一。我们通过对小肠线粒体复合物酶活,呼吸功能,能量物质的含量及荧光定量PCR测定线粒体蛋白编码基因的表达,展示了辐射引起小肠线粒体各指标的变化和相互关系,为能量代谢通路障碍的分子机制提出了进一步的验证。
方法
第一章西藏小型猪急性辐射病模型的建立
选用未去势雄性西藏小型猪为动物模型(n=54),实验组用直线加速器分别予2、5、8、11、14Gy单次剂量照射(n=9/组),剂量率均统一为255cGy/min。对照组9只未予照射。观察西藏小型猪辐射后呕吐、腹泻,大便隐血、外周血淋巴细胞计数及淋巴结淋巴细胞凋亡等指标,分别于照射后6、24、72小时予西藏小型猪分别处死实验组中的三只小型猪,光镜及电镜观察不同剂量不同时间点下西藏小型猪小肠及淋巴结的形态学变化。根据临床现有的辐射病分级标准,比较不同剂量辐射后小型猪的症状与人类急性放射病模型的特点,确定西藏小型猪急性辐射病模型的成功建立。数据分析采用析因法对外周血淋巴细胞计数,淋巴结淋巴细胞凋亡率进行分析。如剂量、时间因素的交互效应及主效应p值小于0.05,则应分别固定时间因素及剂量因素,并用单因素方差分析法对两者的简单效应进行分析。组内多重比较根据方差齐性结果,分别用最小差值法(LSD)或Games-Howell法进行分析。小肠病理评分结果主要采用K-INDEPENDENT Samples非参数检验法进行检测。所有数据处理均用Statistical Product and Service Solutions13.0(SPSS13.0)软件完成。
第二章PET/CT在急性辐射病中的应用探索
实验动物分组及辐照条件参照第一章,PET/CT扫描方法如下：麻醉后,西藏小型猪静脉注射造影剂一小时后开始扫描。扫描所获图像及数据均通过Xeleris工作站系统进行处理。对FDG摄取的定量主要通过：1)划定目的区域(regions of interest, ROIs),本章目的脏器为小肠。2)通过Xeleris工作站系统自动计算注入的FDG剂量与ROIs之间的比值(%ID)。数据的标准化均由电脑自动完成并以SUV值的形式输出。为使图像更为直观的表现出SUV值的差距,本研究主要应用rainbow伪彩模式并将所生成图片的颜色参照彩图条进行设定。为保证结果的客观真实性,我们做了下列措施：1)注入FDG的量统一以0.11-0.13millicurie/kg/猪进行计算；2)所有的实验用猪在进行PET/CT扫描前,至少禁食8小时保证血糖水平的均一和稳定；3)同时对三个相邻层面的SUV最大值进行扫描收集并用以统计学分析；4)小型猪统一于FDG注射后1小时进行扫描。统计方法如下：数据均以均数±标准差的形式进行表示。用析因分析法对小肠SUV值进行分析。如剂量、时间因素的交互效应及主效应p值小于0.05,则应分别固定时间因素及剂量因素,并用单因素方差分析法对两者的简单效应进行分析。组内多重比较根据方差齐性结果,分别用最小差值法(LSD)或Games-Howell法进行分析。P值小于0.05被视为具有统计学差异(双尾)。
第三章急性辐射病的能量代谢损伤机制
本实验所用的18只成年雄性西藏小型猪来自第一章动物分组中2,5,8,11,14Gy的72小时组及对照组。对照组3只,实验组每组3只,静脉注射速眠新麻醉(0.05ml/kg)后分别接收2,5,8,11,14Gy单次X线照射。于辐射72小时麻醉处死前,进行各项能量代谢指标的测定。能量代谢的观察指标包括线粒体超微结构观察、线粒体呼吸链酶复合物活力的测定、线粒体呼吸功能的测定、高效液相色谱法测定不同类型辐射病小肠腺苷酸含量、不同类型急性辐射病蛋白质编码基因的测定。统计方法均采用单因素方差分析。单位湿重能量物质与单位DNA能量物质与病理积分的相关性采用Spearman法,统计软件为SPSS13.0。
结果
第一章西藏小型猪急性辐射病模型的建立
西藏小型猪在辐射后24小时,72小时的腹泻,呕吐及大便隐血评分均无统计学差异(P值>0.05)。各时间点外周血淋巴细胞计数均随着辐照剂量的增加而降低。与对照组相比,各剂量组之间的差异在72h组最为明显。从形态学来看,各实验组随着剂量的增加,淋巴结的体积缩小,出血明显,淋巴细胞数明显下降。西藏小型猪各剂量组辐射6h淋巴结内每个淋巴小结区域的淋巴细胞数目与对照组无明显差异,但在24h和72h,淋巴结内淋巴细胞的数目随着剂量的升高明显降低,且显示出剂量效应。淋巴结淋巴细胞的凋亡率在各时间点都与对照组有统计学差异(P<0.05),2Gy-11Gy之间随着辐射剂量上升,凋亡率也明显上升。72h时,细胞凋亡率在8Gy-14Gy区间内无统计学差异。除了11Gy,同一剂量6h、24h和72h的凋亡率相比,没有统计学差异。各时间点,11Gy组的凋亡率是最高的。辐射后,分别于6小时,24小时和72小时处死不同剂量组的3只西藏小型猪,肉眼观察到不同剂量组各时间点小肠组织变化没有明显差异。照射后6小时即能观察到小肠组织的损伤,但总体来说72小时病变更为明显直接。2Gy组和对照组的小肠组织没有明显不同,5Gy组观察到小肠黏膜面基本平滑,绒毛和皱襞消失,肠壁变薄,小血管扩张、水肿和充血、出血、血淤滞、微血栓、有散在小片状或点状出血。8Gy及11Gy出血多呈斑点状,发生广泛或弥漫性出血,有1只动物观察到肠道大量出血性积聚和血凝块。14Gy组所有动物都出现肠黏膜面大范围的弥漫性出血或肠腔内积血,绒毛上皮发生广泛坏死,黏膜枯萎,肠绒毛裸露。病理结果的半定量积分评估分析,发现病理积分随着剂量的增加明显增加,剂量效应大于时间效应。电镜观察淋巴结细胞的超微结构在11Gy之前组均显示典型的凋亡细胞形态结构。例如,浓缩的染色质及早期染色质边缘集中,中期典型的新月体和环状染色质,细胞质细胞器紧贴,晚期细胞皱缩及凋亡小体。电镜下可见其变化主要表现为细胞核异常(核固缩；核破裂、核溶解等改变,异染色质边缘化,异染色质增多或减少)、小肠绒毛缺失。且变化程度均随放射剂量的增加而增加。11-14Gy的形态学结果显示除了凋亡,组织主要显示出坏死的典型特征。
第二章PET/CT在急性辐射病中的应用探索
照射剂量因素及观察时间点因素对小肠FDG摄取的影响具有显著性。剂量因素、时间因素及两者的交互效应p值均小于0.05)固定时间因素可知：放射后6小时,2Gy组(1.15±0.16)、5Gy组(1.36±0.18)SUV值相较于对照组(1.16±0.26)无统计学差异(2、5Gy组vs对照组,p值均>0.05),8Gy组(2.56±0.38)、11Gy组(2.81±0.28)、14Gy组(1.47±0.31)SUV值均高于对照组(1.16±0.26)有统计学差异,11Gy时达到最高点。
放射后24小时,2Gy组(1。19±0.15)、5Gy组(2.25±0.16)、8Gy组(4.25±0.32)SUV值较对照组是依次升高的趋势(5、8Gy组vs对照组,p值均小于0.05),这个时间点SUV值的最高点出现在8Gy,11Gy组(2.20±0.12)开始低于8Gy、14Gy组(0.76±0.14)SUV值更下降到低于对照组(11Gy组、14Gy组vs对照组p值均小于0.05)。各剂量组之间比较有统计学差异(2Gy组vs5Gy组、5Gy组vs8Gy组、8Gy组vs11Gy组,所有p值均小于0.01),但11Gy组及14Gy组间并无统计学差异(11Gy组vs14Gy组,p值大于0.05)；总体来说24h时间点,SUV值的最高点出现在8Gy,低于8Gy时SUV值随剂量的增加而升高,高于8Gy随着剂量的升高而降低。
放射后72小时,2Gy组(1.84±0.24)、5Gy组(2.93±0.43)SUV值较对照组(1.16±0.10)明显升高(2、5Gy组vs对照组,p值均<0.05),8Gy组(7.03±0.91)、11Gy组(4.09±0.43)SUV值高于对照组且有统计学差异,反之,14Gy组(0.42±0.09)SUV值明显低于对照组(11、14Gy组vs对照组,p值均<0.05),但11、14Gy组SUV值无统计学差异(11Gy vs.14Gy, p>0.05).固定剂量因素可知：放射剂量为2、5、8Gy时,FDG摄取在放射后24及72小时均高于放射后6小时。其变化趋势为放射后24小时FDG摄取>72小时>6小时。放射剂量为11、14Gy时,FDG摄取随观察时间的延长而进行性降低。
第三章急性辐射病的能量代谢损伤
电镜下放射后72小时小肠超微结构进行观察,其变化主要表现为细胞核异常(核固缩；异染色质边缘化；异染色质增多或减少)、线粒体扩张及空泡化。酶活结果表明,复合酶物Ⅰ,Ⅱ,Ⅲ,Ⅳ辐射后72小时的趋势大致相同。复合物酶Ⅰ各实验组与对照组均有显著性差异(P值<0.05),在2-8Gy酶活性明显降低,2Gy,5Gy,8Gy组之间有显著性差异(P值<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅱ2Gy与对照组无显著性差异,2G,5Gy,8Gy组之间有显著性差异(P值<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅲ2Gy与对照组有显著性差异(P值<0.05),其余组与对照组的显著性P值<0.01,2Gy与5Gy之间的差异P值小于0.01,5Gy和8Gy组之间有显著性差异(P<0.05),8Gy,11Gy,14Gy组之间无差异；复合物酶Ⅳ的变化与复合酶Ⅱ相似,低剂量辐射时,无显著性变化,从5Gy开始有明显下降,最明显的变化出现在2-5Gy之间(P<0.01)。与对照组比较,实验组两条呼吸链R3、P/0及RCR均随着剂量的增加显著降低,R4随着剂量增加而增加,说明辐射导致小型猪小肠线粒体呼吸功能下降,氧化磷酸化偶联作用松弛。8Gy以下,各组组间变化明显,超过8Gy之后,呼吸功能无明显变化。不同放射剂量X线辐射后72小时小肠ATP、ADP、AMP和TAN含量(nmol/g湿重)均有显著变化且变化各具特点。(p值均小于0.01)我们发现ATP、ADP和TAN含量在2Gy到8Gy之间随着辐射剂量的增加而降低,显示出剂量效应,而8Gy之后各组腺苷酸含量之间的无统计差异。小肠线粒体能量物质与DNA的比值与单位湿重能量物质的含量趋势一致,表明能量代谢是细胞损伤的机制之一。单位湿重小肠能量物质含量与单位DNA能量物质含量与病理积分的相关性比单位湿重能量物质的变化和病理改变更加紧密。各能量物质中,TAN含量的改变和病理变化相关性最高。RT-PCR结果表明,与线粒体相关的13个基因在辐射后72小时的趋势大致相同。各实验组的表达量均与对照组显著差异,低于8Gy,各剂量组之间显著性差异,各基因的表达量明显大幅度降低,显示出剂量效应。8Gy组的表达量仅为正常组的20%左右,而高于8Gy的实验组之间无显著性差异。
结论：
第一章西藏小型猪急性辐射病模型的建立
1、我们在2Gy-14Gy的辐射区间内成功复制出西藏小型猪不同剂量的急性辐射病模型,小型猪辐射后外周血淋巴细胞计数、细胞凋亡率、病理变化和人类急性辐射病症状非常相似,可以作为急性辐射病的动物模型。
2、根据病理和超显微结构的观察,西藏小型猪不同剂量的急性辐射病的损伤机制存在不同,有待进一步的探索。
第二章PET/CT在急性辐射病中的应用探索
1、不同时间点,PET/CT检测不同剂量组西藏小型猪急性辐射病模型,SUV值的趋势相同,均为先上升,再下降。拐点位置在8Gy。结合患者的临床症状,SUV值可作为急性辐射病诊断和预后的参考。
2、低剂量辐射后SUV值升高可能由于机体的炎症反应导致,高剂量辐射后SUV值降低主要原因为机体遭到极大损伤,组织结构破坏严重,出现坏死,生物体能量代谢障碍。
第三章急性辐射病的能量代谢损伤
辐射导致小肠线粒体能量生成障碍的发生是多环节、多组分共同作用的结果,辐射剂量低时,能量代谢仍能维持一定水平时,但没有完全失衡,细胞功能仍有恢复的可能；当能量物质下降到一定程度时,恢复的几率大大降低。呼吸链复合物酶活性的降低、氧化与磷酸化脱偶联加强、呼吸功能降低,mt DNA的损伤以及能量物质的改变等,均起一定的作用,这些组分均可能成为提高辐射后线粒体能量生成效率的有效干预靶点。
Purpose and background:
The influence of nuclear terrorism, nuclear contamination and nuclear radiation therapy to human survival,safety and health has become a hot topic of current medical research. Large-scale nuclear accident or nuclear terrorist incident may result in a large number of casualties in a short time. The victims radiated by high-dose in a short time are often accompanied by symptoms of systemic reaction, such as systemic, inflammation, nausea, vomiting, septicemia, and skin burns. Due to there is no obvious features of these symptoms, coupled with the clinical work by the personnel nuclear radiation damage is not very common, when in the situation of dealing with such a victim, most of clinical staff dose not have a clear understanding on how to diagnosis the patient's injury and take what kind of active treatment measures. In addition, there are still over200,000cancer patients undergoing radiotherapy all over the world annually, even more than about1.5million of the survival of patients with symptoms of intestinal radiation damage after radiotherapy. Small intestinal tissue radiation toxicity remains a major obstacle to the treatment of abdominal and pelvic tumors, limiting the use of high therapeutic doses. In view of this, a detailed understanding of the intestinal tract to ionizing radiation damage mechanisms and diagnostic methods is very necessary to help taking the effective means to reduce the intestinal damage caused by the clinical course of treatment and improve quality of life in patients.
18-fluoro glucose positron emission tomography/computed tomography X-ray photographic method.(([18F]-FDG-PET/CT) is an advanced molecular imaging diagnostic techniques. This machine combines molecular mechanism,functional analysis, metabolic imaging with classic anatomy, shape, density not only retains the classic role of the anatomical images, and also joined the functionality of advanced molecular imaging, is of great significance for clinical diagnosis. At present, oncology diagnosis in its clinical applications occupied more than90%in this field, mainly used for early detection or exclusion of tumor. However, However, whether [18F]-FDG-PET/CT can be useful in the diagnosis in acute radiation injury is rarely reported. In theory, when the body expose to varying degrees of ionizing radiation, systemic inflammatory response may occur and energy metabolism pathways would be change to some extent, thus will inevitably lead to the change of [18F]-FDG uptake. But is this changes in[18F]-FDG uptake in TBI-induced radiation damage with regularity? Can it be used for rapid diagnosis of exposure doses and reflect the extent of the damage of the body? Which is one of the subject to solve the problem.
The principle on PET/CT for the diagnosis of acute radiation sickness is closely related to the pathogenesis of acute radiation sickness and energy metabolism abnormalities. Mitochondria are the structural basis of the small intestine energy metabolism, the most important part of cell aerobic oxidation in the process for the synthesis of ATP, and also the most radiation sensitive organelles. Through the measurement of small intestine mitochondrial complex activity, respiratory function, the contents of the energy substances and the quantitative PCR determination of expression of the mitochondrial protein coding, gene, we plan to show a radiation-induced changes in indicators of the small intestine, on the basis of the above assumption we can also bring out some hypothesis of the possible molecular mechanism of energy metabolism damage further.
Methods:
Chapter one:The establishment of Tibet mini pig model
The establishment of acute radiation disease model of Tibet mini-pigs. Not castrated male Tibetan mini pig was chose as an animal model (n=54), the radiation groups were exposed to the of2,5,8,11,14Gy of single dose of irradiation (n=9/group) with a linear accelerator, the dose rate was255cGy/min.9of the control group were not irradiated. We recorded vomiting, diarrhea, fecal occult blood, peripheral blood lymphocyte count and lymph node lymphocyte apoptosis index of Tibet mini pigs. Three Tibet mini pigs of the experimental group were sacrificed at6,24,72hours after irradiation respectively, we ovserved the morphological changes of small intestine and lymph nodes by light and electron microscope at different time points. Based on the existing clinical grading standards of acute radiation disease, we classified the symptoms of mini pigs in the different doses of radiation corresponds to a different classification of human acute radiation sickness model, and determine the successful establishment of the
Tibet mini pigs of acute radiation disease model.
The data of peripheral blood lymphocyte count, lymph node and lymphocyte apoptosis were analyzed by repeated measure variance analysis. When interaction effects of factors such as dose, time and the main effect of p-value were less than0.05, variance such as time factors, dose factors or the simple effect of both single-factor should be fixed to analysis.According to multiple comparisons of the homogeneity of variance results within the groups,the minimum difference method (LSD) or Games-Howell method was used for further analysis. K-INDEPENDENT the samples of non-parametric test was applied in intestinal pathological findings. All the data have to deal with are using the Statistical the Product and Service Solutions13.0(SPSS13.0) software.
ChapterⅡ The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
Experimental animal group and the irradiation conditions were the same as the chapter one mentioned. PET/CT scanning methods as follows:After anesthesia, PET/CT begin scanning one hour after intravenous contrast agent to mini pigs. Images and data obtained from scanning further processed through Xeleris work station system. Quantitative FDG uptake mainly through:1, Deline the regions of interest (regions of interest, ROIs), this chapter is mainly for the small intestine.2, Xeleris workstation system can automatically calculates the ratio (%ID) of the injected dose between regions of interest.Standardization and correction of data was automatically performed by computer and output in the form of SUV values..In order to make the image more vividly present the gap between different SUV values,we set up rainbow pseudo-color mode and transferred the PET/CT image into color reference according to the color pictures bar. To ensure the objectiveness and authenticity of results, following measures had been done:1) the amount of FDG injected into Tibet mini pig is0.11-0.13millicurie/kg/pig,2) In order to control blood sugar levels all experimental pigs at least faste eight hours before the PET/CT scan,3) We recorded maximum SUV value of three adjacent scanning levels for further statistical analysis.4) All mini pigs are scanned one hour after the injection of FDG. Statistical methods are as follows:The data are presented as mean±standard deviation. SUV value were analyzed by repeated measure variance analysis. When interaction effects of factors such as dose, time and the main effect of p-value were less than0.05, variance such as time factors, dose factors or the simple effect of both single-factor should be fixed to analysis.
According to multiple comparisons of the homogeneity of variance results within the groups,the minimum difference method (LSD) or Games-Howell method was used for further analysis. P values less than0.05was considered statistically significant (two-tailed). The small intestine SUV and pathological damage degree of correlation analysis using Spearman method.
Chapter III Injury mechanisms of energy metabolism in acute radiation sickness
18adult male Tibet mini pigs used in this experiment came from the72hours subgroup in groups of2,5,8,11,14Gy and control group which were used in chapter one. The experimental group were3pigs while the control one is the same.72hours after radiation pigs were sacrificed, we determine the related energy metabolism indicators. The energy metabolism indicators includes the observations of mitochondrial ultrastructural, the mitochondrial respiratory chain enzyme complex activity,mitochondrial respiratory function,adenylate content of the small intestine by high performance liquid chromatography (HPLC) method,the copies of protein-coding genes.
Results
Chapter I:The establishment of Tibet mini pig model
24hours and72hours after radiation, the data of diarrhea, vomiting and fecal occult blood score Tibet mini pig were not statistically different (P>0.05). At all time points in peripheral blood lymphocyte counts were reduced with increasing radiation dose. Compared with the control group, the differences between each dose group is most obvious in the72h group. Overall, in all experimental groups with increasing dose, lymph nodes became smaller in size, bleeding was more severe, the lymphocyte count decreased significantly. The number of lymphocytes ineach lymphoid nodule area in the Tibet mini pig6h after radiation has no significant difference. At24h and72h, the number of
lymphocytes in lymph nodes decreased significantly with the increasing dose, and showed a dose-response. Lymphocytes apoptosis rate in lymph node and the control group at each time point has significant difference (P<0.05), with the increase in radiation dose between the2Gy-11Gy, the apoptosis rate increase signicicantly. At72h, the apoptosis rate has no significant different between the range of8Gy-14Gy. Except for11Gy, the same dose at6h,24h and72h, the apoptosis rate has no statistical significance. At each time point, the apoptosis rate of11Gy group is the highest,6hours,24hours and72hours after radiation, three Tibet mini pigs from different dose groups were sacrificed respectively, there is no significantly difference in different time point of the same dose in visual observation of the intestinal tissue.
visual observation to the intestinal tissue changes of the different dose groups at each time point has no significant difference., We can observe small intestinal tissue injury as early as6hours after irradiation, however, on the whole, lesions in72hours was more obvious and direct. Intestinal tissue of2Gy group and control group was not significantly different. We found that the small intestine mucosa surface was basically smooth in5Gy group,but we can also found the villi became sparse and short, the small vascular expanded and there was dot like bleeding.8Gy and11Gy bleeding became more severe and found blood blot extensively. In14Gy group, all animal showed extensive bleeding, blood blot and diffuse hemorrhage in the mucosal surface of intestine, chorioepithelium appeared extensive necrosis, hardly no villi can be saw and intestinal villi hardly gone. The semi-quantity score of pathology showed an increase trend with dose increase, and the dose effect was more obvious than time effect. The ultrastructure of intestine and lymph note showed typical apoptosis cell state before dose of11Gy, we can see the typical apoptosis cell indicators such as concentrated and edging of chromatin at early phase, Crescent and ring chromatin at the media phase and apoptotic bodies at the late phase. While at14Gy the ultrastructure showed typical necrosis in the both organs.
ChapterⅡ The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
Factors such as radiation dose and observation time both have significant influence on FDG uptake of intestine. The main-effects of time and radiation dose, and their cross-over effect were less than0.05. To the simple effect of radiation dose, at6h post-TBI, small-intestinal FDG uptake in2and5Gy showed no difference from control group, while those in8,11and14Gy were higher than control group. At24h post-TBI, small-intestinal FDG uptake showed no difference between2Gy-group and control group. Those in5,8and11Gy-group were higher than control group, while those in14Gy-group was lower than control group. It should be noted that on the time-points of6and24h post-TBI, FDG uptake in2,5and8Gy increased with the increase of radiation doses, while the reverse trend were shown in the following doses. At72h post-TBI, small-intestinal FDG uptake showed a radiation dose-dependent increase in the dose range of2to8Gy, while the rapid and marked decreases were shown in11and14Gy-group. To the simple effect of time-points, small-intestinal FDG uptake increased with the time prolonging in2,5and8Gy-group, while the reversed trend was shown in11and14Gy-group.
Chapter III Injury mechanisms of energy metabolism in acute radiation sickness
The main morphology of intestine under TEM was the abnormal of nuclear.(the condensed nucleus, the edging of heterochromatin, increased or reduced heterochromatin),the expand and vacuolization of mitochondria. The results of enzyme complexes activities showed, enzyme complex Ⅰ,Ⅱ,Ⅲ and IV at72h after radiation almost the same trend. The complex I in all experiment group has significant difference with the control group.(P<0.05), its activity decreased sharply at2-9Gy and there are significant differences between dose group2-8Gy, while from8-14Gy there was no significant different among them. Complex II has no significant difference between2Gy group and control group, however, there were significant difference in the range of2-8Gy,the later dose group show the same trend with complex I.The P value of complex III in2Gy and control is less than0.05,while the other group was0.01. The change of complex IV was almost the same as complex II, which didn't change until5Gy, then there is a sudden drop from5Gy.
Compared with control group, the value of R3,P/O, and RCR is decreasing with increase dose, which means the dysfunction of mitochondrial respiratory chain and relaxation of oxidative Phosphorylation.8Gy is the key point, that prior to 8Gy the following change is evident, while no significant changes in respiratory function when the dose is more than8Gy.72hours after X-ray radiation, the ATP, the ADP, AMP, and TAN content (nmol/gwet weight) of different doses of radiation in small intestine are significantly changing and has its own change characteristics respectively.(P-value is less than0.01). We found that ATP, ADP, and TAN content decreases with increasing radiation dose in2Gy to8Gy, showing a dose effect, but after8Gy, no statistical difference between the group of adenylate content. The ratio of mitochondrial energy substances and DNA in small intestine and energy substances trends, indicating that energy metabolism is one of the mechanisms of cell injury. Compared with the energy of the unit wet weight of the small intestine material content, the relationship of unit DNA-energy matter content with pathological integral unit wet weight of energy material changes and pathological changes was more closely. Of all energy materials, the changes of TAN content has the closest relationship with pathological changes. RT-PCR results showed that the trend of the13genes associated with mitochondria encoding protein in the72hours after irradiation were almost the same. Significant differences existed in expression levels for each experimental group and control group less than8Gy, there are significant differences between each dose group, the amount of gene expression is obviously reduced, showing a dose effect. The expression of8Gy group only about20%of the normal group, but higher than8Gy, there is no significant difference among the experimental group.
Conclusions:
Chapter I:The establishment of Tibet mini pig model
1、We successfully established different stages of acute radiation sickness in Tibet mini pig model at range of2Gy-14Gy radiation
2、Based on pathology and ultrastructure observation, there is different injury mechanism in Tibet mini pig at different stages of acute radiation sickness, we need to further explore.
Chapter Ⅱ:The exploration of diagnosis value of PET/CT in acute radiation disease in Tibet mini pig model
1、At different time points, we use PET/CT to detect the different dose groups in Tibet mini pigs with acute radiation sickness model, the same trend of SUV values were first increased and then decreased. Inflection point location is about5Gy to8Gy. It proves that PET/CTdoes not apply to the determination of the radiation dose acute radiation sickness.
2、We speculated that in the case of the presence of inflammation, the reason that the SUV value even decrease may be the possibility of reduced glucose metabolism due to obstacle in organism energy metabolism is much greater than the increased glucose metabolism trigered by inflammation.
Chapter Ⅲ Injury mechanisms of energy metabolism in acute radiation sickness
Radiation-induced intestinal mitochondrial energy generation obstacle is the result of multi-link, multi-component. If the radiation dose is not lethal, energy metabolism can still maintain a certain level, but not completely off balance, cell function may recover. When the energy of the material drop to a certain extent, the chance of recovery is greatly reduced. The decrease of respiratory chain complex activity, the strengthen uncoupling of oxidative phosphorylation,the reduction of respiratory function and mtDNA damage as well as the energy changes of substance, all play a role in mitochondrial energy production, which to improve to be an effective intervention target.
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