高剂量电离辐射对恒河猴器官组织病理改变及相关细胞因子表达的影响
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摘要
放射治疗已成为治疗肿瘤的一种重要方法,但在治疗同时,高剂量的电离辐射会对机体各个组织器官造成损伤。为探讨高剂量电离辐射对恒河猴(Macaca mulatta)心、肝、脾、肺、肾及肠道组织的病理性损伤及相关细胞因子表达的影响,本研究用辐射能量9.5 Gy的60Coγ对3只雄性恒河猴照射4 h,于辐射后15 d处死并采集相关器官组织,采用苏木精-伊红染色(hematoxylin-eosin staining,HE)观察心、肝、脾、肺、肾及肠道组织病理损伤情况,同时采用免疫组化和图像分析技术检测各组织内肿瘤坏死因子-α(tumor necrosis factor-α,TNF-α)、白介素-6(interleukin-6,IL-6)、IL-10、IL-2和转化生长因子β1(transforming growth factorβ1,TGF-β1)的表达。结果表明,辐射后15 d,跟对照相比,恒河猴心、肝、脾、肺及肾组织发生明显病理变化,而且TNF-α、IL-6、IL-10、IL-2和TGF-β1表达量显著高于对照组(P<0.05),说明电离辐射所致的放射性损伤对相关细胞因子表达有影响,研究结果可为放射性损伤的诊断提供辅助参考。
Radiation therapy has become an important method of treating tumors,but at the same time,high doses of ionizing radiation can cause damage to the tissues and organs.To study the effects of high-dose ionizing radiation on the pathological injury and related cytokine expression in the heart,liver,spleen,lung,kidney and intestinal tract of rhesus monkey(Macaca mulatta),three male rhesus monkeys were irradiated with 9.5 Gy of ~(60)Co γ for 4 h,and the organs were sacrificed 15 days after irradiation.The pathological changes of heart,liver,spleen,lung,kidney and intestinal tissues were observed by hematoxylin-eosin staining(HE).The expression of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-10,IL-2 and transforming growth factor β1(TGF-β1) in each tissue were detected by immunohistochemistry and image analysis.The results showed that the heart,liver,spleen,lung and kidney tissues of treated rhesus monkeys had obvious pathological changes compared with the control,and the expression of factors was significantly higher than that of the control group(P<0.05) at 15 days after irradiation.This indicates that radioactive injury caused by ionizing radiation has an effect on the expression of related cytokines.The results of the study provide a supplementary reference for the diagnosis of radioactive injury.
Radiation therapy has become an important method of treating tumors,but at the same time,high doses of ionizing radiation can cause damage to the tissues and organs.To study the effects of high-dose ionizing radiation on the pathological injury and related cytokine expression in the heart,liver,spleen,lung,kidney and intestinal tract of rhesus monkey(Macaca mulatta),three male rhesus monkeys were irradiated with 9.5 Gy of ~(60)Co γ for 4 h,and the organs were sacrificed 15 days after irradiation.The pathological changes of heart,liver,spleen,lung,kidney and intestinal tissues were observed by hematoxylin-eosin staining(HE).The expression of tumor necrosis factor-α(TNF-α),interleukin-6(IL-6),IL-10,IL-2 and transforming growth factor β1(TGF-β1) in each tissue were detected by immunohistochemistry and image analysis.The results showed that the heart,liver,spleen,lung and kidney tissues of treated rhesus monkeys had obvious pathological changes compared with the control,and the expression of factors was significantly higher than that of the control group(P<0.05) at 15 days after irradiation.This indicates that radioactive injury caused by ionizing radiation has an effect on the expression of related cytokines.The results of the study provide a supplementary reference for the diagnosis of radioactive injury.
引文
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高林峰,王洪复,朱飞鹏.2004.电离辐射肾损伤病理特点及其机理研究[J].中华放射医学与防护杂志,24(5):430-432.(Gao L F,Wang H F,Zhu F P.2004.Pathological characteristics and mechanism of renal injury induced with ionizing radiation[J].Chinese Journal of Radiological Medicine and Protection,24(5):430-432.)
黄璟,周毅.2015.肿瘤坏死因子α及其抑制剂的研究进展[J].国际口腔医学杂志,42(1):63-68.(Huang J,Zhou Y.2015.Research progress on tumor necrosis factor a and its inhibitors[J].International Journal of Stomatology,42(1):63-68.)
龚兆丽.2016.胸部放射治疗对心脏损伤的临床研究[J].世界临床医学,10(13):42,44.(Gong Z L.2016.Clinical study of chest radiotherapy on cardiac injury[J].World Journal of Clinical Medicine,10(13):42,44.)
刘崟,金伯泉.1992.猕猴细胞免疫功能检测的研究进展[J].实验动物与比较医学,(1):18-20.(Liu Y,Jin B Q.1992.Research progress of cellular immune function in macaques[J].Laboratory Animal and Comparative Medicine,(1):18-20.)
马晓薇.2013.牛磺酸及血管紧张素转化酶抑制剂对大鼠急性肺损伤的保护作用研究[D].重庆医科大学,硕士学位论文,导师:罗永艾,pp.47-57.(Ma X W.2013.Protective effects of taurine and angiotensin converting enzyme inhibitor on acute lung injury in rats[D].Chongqing Medical University,Thesis for Ph.D.,Supervisor:Luo Y A,pp.47-57.)
(美)Mayer主编.2013.肿瘤放疗最新进展[M].人民军医出版社,379.(John L.Meyer.2013.Advances in the Treatment Planning and Delivery of Radiotherapy[M].People's Military Medical Press,379.)
孙宝娲,董娟聪,王金虎,等.2011.电离辐射对小鼠免疫器官不同亚群T淋巴细胞调节因子的影响[J].吉林大学学报医学版,37(6):985-988.(Sun BW,Dong J C,Wang J H,et al..2011.Effects of ionizing radiation on T lymphocyte regulatory factors in different subgroups of immune organs in mice[J].Journal of Jilin University Medicine,37(6):985-988.)
唐瑛,孙欢,岳峰,等.2013.大剂量电离辐射对小鼠肺组织的影响[J].中国实验动物学报,21(1):67-69.(Tang Y,Sun H,Yue F,et al.2013.Effects of high-dose ionizing radiation exposure on the lung tissue in mice[J].Acta Laboratorium Animalis Scientia Sinica,21(1):67-69.)
王静,王平,庞青松,等.2009.非小细胞肺癌三维适形放疗放射性肺损伤临床及剂量学因素分析[J].中华放射肿瘤学杂志,18(6):448-451.(Wang J,Wang P,Pang Q S,et al.2009.Non-small cell lung cancer three-dimensional conformal radiotherapy radioactive lung injury clinical and dose factors analysis[J].Chinese Journal of Radiation Oncology,18(6):448-451.)
吴戈,肖蕾,艾尼瓦尔·艾木都拉.2014.放射性肝纤维化的实验研究中TNF-α、NF-κB p65和TGF-β1动态变化及表达意义[J].中华放射肿瘤学杂志,390-391.(Wu G,Xiao L,N Ni-wa-er·AI mu-du-la.2014.Dynamic changes and expression of TNF-α,NF-κB p65 and TGF-βin the experimental study of radiation induced liver fibrosis[J].Chinese Journal of Radiation Oncology,390-391.)
吴戈,肖蕾,张瑞丽,等.2015.急性放射性肝损伤大鼠模型的建立与评价[J].中国实验动物学报,(2):178-181.(Wu Y,Xiao L,Zhang R L,et al.2015.Establishment and evaluation of a rat model of acute radioation-induced liver injury[J].Acta Laboratorium Animalis Scientia Sinica,(2):178-181.)
周游,李浪,陈绘颖,等.2014.大鼠放射性心脏损伤后肿瘤坏死因子α表达的变化及阿托伐他汀对其的影响[J].中华老年心脑血管病杂志,16(7):751-753.(Zhou Y,Li L,Chen H Y,et al.2014.Effect of atorvastatin on expression of TNF-αin rats with heart injury following irradiation[J].Chinese Journal of Geriatric Heart Brain and Vessel Diseases,16(7):751-753.)
Arpin D,Perol D,Blay J Y,et al.2005.Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis[J].Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology,23(34):8748-8756.
Boerma M.2012.Experimental radiation-induced heart disease:Past,present,and future[J].Radiation Research:Official Organ of the Radiation Research Society,178(1):1-6.
Drabek T,Janata A,Wilson C D,et al.2014.Minocycline attenuates brain tissue levels of TNF-αproduced by neurons after prolonged hypothermic cardiac arrest in rats[J].Resuscitation,85(2):284-291.
Hehlgans T,Pfeffer K.2005.The intriguing biology of the tumor necrosis factor/tumour necrosis factor receptor superfamily:Players,rules and the games[J].Immunology,115(1):1-20.
Jung J,Yoon S M,Kim S Y,et al.2013.Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma:Clinical and dose-volumetric parameters[J].Radiation Oncology,8(1):249.
K?st S,D?rr W,Keinert K,et al.2002.Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy[J].International Journal of Radiation Biology,78(8):695.
Rocco Bellantone M D,Maurizio Bossola M D,Merrick HW,et al.1992.Whole liver intraoperative irradiation after partial hepatectomy produces minimal functional and pathologic lesions[J].Journal of Surgical Oncology,50(2):81-88.
Rübe C E,Wilfert F,Palm J,et al.2004a.Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung[J].Strahlentherapie Und Onkologie,180(7):442-448.
Rübe C E,Rodemann H P,Rn H P,et al.2004b.Irradiation induces a biphasic expression of prmental basis and clinical significance[J].Strahlentherapie Und Onkologie,180(9):541-549.
Schett G.2011.Effects of inflammatory and anti-inflammatory cytokines on the bone[J].European Journal of Clinical Investigation,41(12):1361-1366.
Trip A K,Sikorska K,Sandick J W V,et al.2015.Radiationinduced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer[J].Radiotherapy&Oncology,116(2):239-244.
陈暑波,冯军,赵帆,等.2015.大鼠急性放射性肝损伤TGF-β1放射和α-SMA的表达变化[J].中国现代医学杂志,25(1):12-15.(Chen S B,Feng J,Zhao F,et al.2015.Study on TGF-β1 andα-SMA transformation in acute radiation-induced liver disease in rats[J].China Journal of Modern Medicine,25(1):12-15.)
高辉,左斯尧,黄政基,等.2015.不同剂量辐射诱导小鼠胸腺Th1-Th2-Th3型细胞相关基因的功能分析[J].中华放射医学与防护杂志,35(4):248-251.(Gao H,Zuo SY,Huang Z J,et al.2015.Analysis of Th1-Th2-Th3 related gene expressions in the thymus of mice irradiated with different doses[J].Chinese Journal of Radiation Medicine and Protection,35(4):248-251.)
高林峰,王洪复,朱飞鹏.2004.电离辐射肾损伤病理特点及其机理研究[J].中华放射医学与防护杂志,24(5):430-432.(Gao L F,Wang H F,Zhu F P.2004.Pathological characteristics and mechanism of renal injury induced with ionizing radiation[J].Chinese Journal of Radiological Medicine and Protection,24(5):430-432.)
黄璟,周毅.2015.肿瘤坏死因子α及其抑制剂的研究进展[J].国际口腔医学杂志,42(1):63-68.(Huang J,Zhou Y.2015.Research progress on tumor necrosis factor a and its inhibitors[J].International Journal of Stomatology,42(1):63-68.)
龚兆丽.2016.胸部放射治疗对心脏损伤的临床研究[J].世界临床医学,10(13):42,44.(Gong Z L.2016.Clinical study of chest radiotherapy on cardiac injury[J].World Journal of Clinical Medicine,10(13):42,44.)
刘崟,金伯泉.1992.猕猴细胞免疫功能检测的研究进展[J].实验动物与比较医学,(1):18-20.(Liu Y,Jin B Q.1992.Research progress of cellular immune function in macaques[J].Laboratory Animal and Comparative Medicine,(1):18-20.)
马晓薇.2013.牛磺酸及血管紧张素转化酶抑制剂对大鼠急性肺损伤的保护作用研究[D].重庆医科大学,硕士学位论文,导师:罗永艾,pp.47-57.(Ma X W.2013.Protective effects of taurine and angiotensin converting enzyme inhibitor on acute lung injury in rats[D].Chongqing Medical University,Thesis for Ph.D.,Supervisor:Luo Y A,pp.47-57.)
(美)Mayer主编.2013.肿瘤放疗最新进展[M].人民军医出版社,379.(John L.Meyer.2013.Advances in the Treatment Planning and Delivery of Radiotherapy[M].People's Military Medical Press,379.)
孙宝娲,董娟聪,王金虎,等.2011.电离辐射对小鼠免疫器官不同亚群T淋巴细胞调节因子的影响[J].吉林大学学报医学版,37(6):985-988.(Sun BW,Dong J C,Wang J H,et al..2011.Effects of ionizing radiation on T lymphocyte regulatory factors in different subgroups of immune organs in mice[J].Journal of Jilin University Medicine,37(6):985-988.)
唐瑛,孙欢,岳峰,等.2013.大剂量电离辐射对小鼠肺组织的影响[J].中国实验动物学报,21(1):67-69.(Tang Y,Sun H,Yue F,et al.2013.Effects of high-dose ionizing radiation exposure on the lung tissue in mice[J].Acta Laboratorium Animalis Scientia Sinica,21(1):67-69.)
王静,王平,庞青松,等.2009.非小细胞肺癌三维适形放疗放射性肺损伤临床及剂量学因素分析[J].中华放射肿瘤学杂志,18(6):448-451.(Wang J,Wang P,Pang Q S,et al.2009.Non-small cell lung cancer three-dimensional conformal radiotherapy radioactive lung injury clinical and dose factors analysis[J].Chinese Journal of Radiation Oncology,18(6):448-451.)
吴戈,肖蕾,艾尼瓦尔·艾木都拉.2014.放射性肝纤维化的实验研究中TNF-α、NF-κB p65和TGF-β1动态变化及表达意义[J].中华放射肿瘤学杂志,390-391.(Wu G,Xiao L,N Ni-wa-er·AI mu-du-la.2014.Dynamic changes and expression of TNF-α,NF-κB p65 and TGF-βin the experimental study of radiation induced liver fibrosis[J].Chinese Journal of Radiation Oncology,390-391.)
吴戈,肖蕾,张瑞丽,等.2015.急性放射性肝损伤大鼠模型的建立与评价[J].中国实验动物学报,(2):178-181.(Wu Y,Xiao L,Zhang R L,et al.2015.Establishment and evaluation of a rat model of acute radioation-induced liver injury[J].Acta Laboratorium Animalis Scientia Sinica,(2):178-181.)
周游,李浪,陈绘颖,等.2014.大鼠放射性心脏损伤后肿瘤坏死因子α表达的变化及阿托伐他汀对其的影响[J].中华老年心脑血管病杂志,16(7):751-753.(Zhou Y,Li L,Chen H Y,et al.2014.Effect of atorvastatin on expression of TNF-αin rats with heart injury following irradiation[J].Chinese Journal of Geriatric Heart Brain and Vessel Diseases,16(7):751-753.)
Arpin D,Perol D,Blay J Y,et al.2005.Early variations of circulating interleukin-6 and interleukin-10 levels during thoracic radiotherapy are predictive for radiation pneumonitis[J].Journal of Clinical Oncology Official Journal of the American Society of Clinical Oncology,23(34):8748-8756.
Boerma M.2012.Experimental radiation-induced heart disease:Past,present,and future[J].Radiation Research:Official Organ of the Radiation Research Society,178(1):1-6.
Drabek T,Janata A,Wilson C D,et al.2014.Minocycline attenuates brain tissue levels of TNF-αproduced by neurons after prolonged hypothermic cardiac arrest in rats[J].Resuscitation,85(2):284-291.
Hehlgans T,Pfeffer K.2005.The intriguing biology of the tumor necrosis factor/tumour necrosis factor receptor superfamily:Players,rules and the games[J].Immunology,115(1):1-20.
Jung J,Yoon S M,Kim S Y,et al.2013.Radiation-induced liver disease after stereotactic body radiotherapy for small hepatocellular carcinoma:Clinical and dose-volumetric parameters[J].Radiation Oncology,8(1):249.
K?st S,D?rr W,Keinert K,et al.2002.Effect of dose and dose-distribution in damage to the kidney following abdominal radiotherapy[J].International Journal of Radiation Biology,78(8):695.
Rocco Bellantone M D,Maurizio Bossola M D,Merrick HW,et al.1992.Whole liver intraoperative irradiation after partial hepatectomy produces minimal functional and pathologic lesions[J].Journal of Surgical Oncology,50(2):81-88.
Rübe C E,Wilfert F,Palm J,et al.2004a.Irradiation induces a biphasic expression of pro-inflammatory cytokines in the lung[J].Strahlentherapie Und Onkologie,180(7):442-448.
Rübe C E,Rodemann H P,Rn H P,et al.2004b.Irradiation induces a biphasic expression of prmental basis and clinical significance[J].Strahlentherapie Und Onkologie,180(9):541-549.
Schett G.2011.Effects of inflammatory and anti-inflammatory cytokines on the bone[J].European Journal of Clinical Investigation,41(12):1361-1366.
Trip A K,Sikorska K,Sandick J W V,et al.2015.Radiationinduced dose-dependent changes of the spleen following postoperative chemoradiotherapy for gastric cancer[J].Radiotherapy&Oncology,116(2):239-244.