【作者】 王静；

【导师】 王平； 朱莉； 袁智勇； 庞青松；

【作者基本信息】 天津医科大学 ， 肿瘤学， 2008， 硕士

【摘要】 目的:建立定量肺体积大鼠放射性肺损伤动物模型,比较“大剂量小体积”与“小剂量大体积”放疗引起放射性肺损伤的异同,探讨放射性肺损伤剂量体积关系。方法:运用ELEKTA precise 2.03治疗计划系统建立定量肺体积大鼠放射性肺损伤动物模型,确定各实验组放疗剂量及体积,应用医用直线加速器实施放疗,放疗后观察16周。各实验动物放疗前1周内及放疗后每2周分别称体重、计数呼吸频率变化情况,眼眶静脉丛取血行ELISA检测血浆TGF-β1含量。放疗后第4、8、16周行胸CT扫描,并分批处死实验动物,制备肺组织石蜡切片,行HE染色,免疫组化检测组织中TGF-β1表达情况。结果:1、定量肺体积大鼠放射性肺损伤模型:(1)“大剂量小体积”组:前后两野对穿,SAD=100cm,6MVX,照射体积1.748cm~3(25%肺体积),照射剂量DT=4610cGy,单次;(2)“小剂量大体积”组:前后两野对穿,SAD=100cm,6MVX,照射体积6.99cm~3(100%肺体积),照射剂量DT=2000cGy,单次;2、放疗前后体重变化情况:接受放疗后的两实验组大鼠体重出现不同程度的增长延缓(2—16周,p＜0.05),对照组＞“大剂量小体积”组(25%组)＞“小剂量大体积”组(100%组);3、放疗前后呼吸频率变化情况:接受放疗后的两实验组均出现呼吸频率加快,第6—8周达峰值,此后下降,对照组＜25%组＜100%组(p＜0.05),在此期间5只实验动物死于呼吸衰竭,其中4只为100%组而25%组仅1只;4、胸CT:放疗后第4周即出现影像学改变,第8周时最严重,16周时病变局限。100%组主要以全肺透过度下降,广泛性密度增高为主,而25%组则出现毛玻璃样改变、斑片状高密度影及纤维条索状阴影。未见胸腔积液、胸膜增厚以及肺萎陷等征象;5、ELISA:放疗后2—4周(25%组为2—6周)血浆TGF-β1含量下降,此后急剧上升,第8周达高峰,随后稍有下降达平稳(25%组则与对照组持平);6、HE:放疗后第4周即出现病理学改变,第8周时最严重,16周时病变稳定。100%组以广泛的肺泡壁增厚、血管壁水肿、硬化为主、肺实质损伤相对较轻;25%组以局限性红细胞及炎细胞渗出为主,血管肺实质损伤较重;7、免疫组化:对照组TGF-β1呈不表达或低表达。放疗后第4周接受放疗的两组动物肺组织即出现TGF-β1表达增多:对照组＜25%组＜100%组(p＜0.05);第8周时TGF-β1表达有所下降,100%组与25%组之间p＞0.05,但均与对照组存在差异;第16周时25%组与对照组未见差异,而上述两组均与100%组存在差异。结论:1、应用ELEKTA precise 2.03治疗计划系统建立定量肺体积大鼠放射性肺损伤动物模型具有可行性;2、“小剂量大体积”与“大剂量小体积”放疗模式引起的放射性肺损伤在发生、发展以及转归等诸多方面存在差别;3、“小剂量大体积”照射的大鼠一般情况及肺功能损伤明显,放射性肺损伤发生较早且较严重;“大剂量小体积”照射的大鼠肺组织局部病理损伤明显,但由于周围正常肺组织代偿,故放射性肺损伤的发生相对较晚且较轻;4、放疗后定期的影像学检查(前半年内每月1次)有利于放射性肺损伤的提早发现;5、放疗后血浆TGF-β1含量与肺组织TGF-β1表达在时间上及数量上均存在差别,故血浆TGF-β1含量对放射性肺损伤的预测作用有待进一步临床试验研究;6、临床上,将低剂量分散到大体积中去是不安全的,尽管肺功能损害是一过性的,但有可能是致命的,建议运用IMRT技术做胸部放疗时应慎重;7、对于肺组织的放射性损伤而言,照射体积较照射剂量更为重要。预防放射性肺损伤最安全的途径是降低正常肺组织受照剂量的同时降低受照体积。更多还原

【Abstract】 Objective:To investigate the relationships between the irradiation dose and volume in radiation-induced lung injury through setting—up the model of graded volume irradiation of the rat lung.Methods:ELEKTA precise 2.03 treatment plan system was applied to calculate the irradiation dose and volume.Functional,biochemical,histopathological and CT changes were compared biweekly after single irradiation of the regional lung.Results:1.Rat model of lung fibrosis:Single dose irradiation（2000cGy and 4610cGy）to two different volume levels（100%and 25%）were applied to set up the model of graded volume irradiation of the rat lung.2.Weight:Delayed growth was observed after irradiation(2^nd-16^thweeks,p＜0.05). The weight was presented as control group＞100%group＞25%group.3.Breathing rates（BR）:Functionally,both of the 100%and 25%cohorts observed BR increases after irradiation,especially in the period of 6^th-8^thweeks.100%group was earlier and faster.25%group,although pathology was more severe,hardly any obvious increase in BR was observed.In the period of 6^th-8^thweeks 5 rats died of respiratory failure,1 in 25%group and 4 in 100%group.4.Computed tomography image:Radiographic changes were observed in the early period(4^thw)and it comes to the most obvious changes in the mediated period(8^thw). The extensiveness of high density and the decreased lung permeability was presented in 100%group and ground glass opacity,patchy consolidation was presented in 25% group without pleural effusion,pleural thickening and lung shrinking.5.ELISA:Plasma TGF-β1 levels has a transient decrease during 2^nd-4^thweeks after radiation in 100%group following a returning of a higher level from the end of the 4^th week and then reach peak at the 8^thweek.TGF-β1 has a continuous low level in 25% group after radiation.6.HE stain:Morphologicly,100%group was mainly presented as vascular damage which was signed of vascular wall edema,hypertrophy and sclerosis,25%group was mainly presented as erythrocyte cell exudation,inflammation and parenchymal damage.7.Immunohistochemistry:TGF-β1 was observed increased expression at 4^thweek following a retuming of a low level at the 8^thweek.The overall trend was presented as control group＜25%group＜100%group（p＜0.05）.Conclusions:1.Setting up the model of graded volume irradiation of rat lung using ELEKTA precise 2.03 treatment plan system is feasible.2.The mechanism underlying symptomatic radiation-induced lung injury varies depending on time and irradiation volume,with vascular damage at large volume/low doses and parenchymal injury at higher doses and low volume.3.Recoverable vascular damage induced respiratory dysfunction at large volume/low doses and parenchymal injury compensated by normal lung tissue out of irradiation field at higher doses/low volumes.4.Radiographic changes were observed in the early period（4w）which has profit of the early detection of radiation-induced lung injury.5.The level of TGF-β1 was elevated locally at the site of radiation injury,but it did not pass through the vascular endothelium into the general circulation,so increases in plasma levels were not commensurate and homeochronous with the increases in lung tissue,and the predictive power of TGF-β1 needs advanced study.6.Delivery of a small dose of radiation to a large volume is not safe.Low dose smeared out overlarge volumes,albeit reversible,may already give rise to fateful respiratory dysfunction.IMRT delivered low-to-intermediate doses to significant portions of healthy lung and may yield unexpected toxicity,so we therefore recommend caution in the utilization of this technique in lung cancer.7.Damage to the lung may be more dependent on the volume irradiation than on the radiation dose.Clinically,the safest approach is to limit both the volume of normal lung that is irradiated and the amount of radiation that it receives.更多还原