放射性肝损伤的发病机制及防治策略研究
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摘要
原发性肝癌(PLC)是常见恶性肿瘤,尽管根治手术切除和肝移植仍为肝癌获得根治的主要途径,但80%患者明确诊断后即失去根治手术机会。越来越多确凿临床数据表明肝癌是放射敏感肿瘤。放射性肝损伤(RILD)是继发于肝脏放疗后并发的最严重、制约剂量递增的致死性并发症。肝脏是仅次于骨髓、淋巴组织的放射敏感器官,然而体外肝实质细胞却是放射抵抗细胞,很难用“经典的靶细胞理论”解释。前期研究中已经证实肝实质细胞微环境包括非实质细胞、放疗后产生的细胞因子级联效应参与肝脏放射损伤发生、发展,即放疗后的非靶向性效应(Non-target effect)在RILD中发挥重要作用。辐射诱导基因调控下多条信号传导途径进行细胞内及细胞间的信息传递,形成庞大调控网络,但它们之间的相互关系及调控模式仍不清楚。大量文献支持肝脏非实质细胞是放射敏感细胞,放疗后释放大量细胞因子是放射诱导非靶向性效应的关键因素。已经证实转化生长因子-β(TGF-p)在放射性肝损伤显著活化且高表达,TGF-β信号通路与RILD密切相关,但其确切作用机制仍然不清楚,本研究将在前面研究的基础上通过构建携带目的基因的重组腺病毒基因治疗阻断TGF-β信号通路或抑制Kupffer细胞,研究放射诱导的非靶向性效应与肝脏放射损伤的关系,从全新角度探索RILD分子机制及防控策略。
第一部分应用AdMax系统构建TβIIR-IgFc融合基因重组腺病毒
目的：应用AdMax系统构建携带Ⅱ型TGFβ受体(TβIIR)IgFc融合基因重组腺病毒,为进一步研究放射性肝纤维化干预打下基础。
材料和方法：针对TβIIR设计引物,PCR目的基因TβI IR构建PDC316-TβIIR:针对工gFc设计引物,PCR目的基因IgFc,连入PDC316-T p IIR构建PDC316-TβIIR-IgFc；双质粒共转染293细胞,同源重组产生重组腺病毒,AdMax腺病毒包装系统由骨架质粒：pBHGl ox-E1,3Cre和穿梭质粒：pDC316-2501组成。使用LipOfectam lne2000法转染293细胞包装携带目的融合基因的重组腺病毒,少量提取重组腺病毒DNA检测证实为复制缺陷型TβIIR-IgFc基因重组腺病毒后大量扩增、生产、纯化及鉴定。
结果：PCR扩增TβRII基因,酶切连接到pDC316-cmv-EGFP空载体,提取质粒酶切鉴定电泳检测正确；PCR扩增IgFC基因,酶切、连接PDC316-TβRII载体,再提取质粒,根据PDC316载体序列设计引物,PCR琼脂糖凝胶电泳与预期的目的基因片段一致,测序鉴定正确。双质粒共转染293细胞,转染后第9天出毒而在光学显微镜下观察出毒现象表现为细胞变大变圆,呈“葡萄串”样形态学特征,并开始出现明显噬斑。转染后第14天待细胞大部分病变并从底部脱落进行收毒,证明有感染能力病毒颗粒包装成功。重组腺病毒经RT-PCR扩增后,产物电泳观察出现一条特异性预期条带,证明该重组腺病毒携带目的基因。测得扩增后病毒滴度为2.6×1012pfu／m1。
结论：应用AdMax系统可方便、快捷地构建携带目融合基因的复制缺陷型重组腺病毒。
第二部分抑制TGF-β信号转导通路有效减轻大鼠放射性肝纤维化
目的：本研究拟通过携带可溶性TβIIR的复制缺陷性重组腺病毒(AdTβRIIFc)选择性阻断TGF-β信号转导通路治疗晚期放射性损伤,明确TGF-β在放射性肝纤维化(RILF)发展中作用机制,进一步探索RILF的治疗策略。
方法：RILF大鼠模型采用上腹部全肝30Gy单次照射,放疗后活过6个月的大鼠肝脏都出现晚期纤维化表现。随机分成4组,第1组模型组(RILFM);第2组携带目的基因重组腺病毒基因治疗组：腹腔注射1X1011 PFU AdTβRIIFc;第3组空病毒对照组,腹腔注射相同剂量和滴度的对照病毒；第4组生理盐水对照组,腹腔注射等体积的生理盐水(SALINE).
结果：抑制TGF-β信号转导通路有效抑制放射性诱导肝星状细胞(HSC)活化、胶原蛋白-1(Col-I)和纤维粘连接蛋白(Fibronectin, FN)表达；阻断TGF-β信号转导通路可以减轻RILF阶段慢性氧化应急(Chronic Oxidative Stress, COS) DNA损伤。另外,抗TGF-β治疗可以有效释放TGF-β对肝细胞生长抑制效应,提高肝细胞代偿能力,有效缓解RILF对肝脏功能损伤。
结论：TGF-β信号转导通路在RILF的形成和发展中发挥重要作用,阻断TGF-β信号转导通路有效缓解RILF。
第三部分抑制肝脏Kupffer细胞减轻放射诱导肝脏细胞凋亡
目的：通过放疗前三氯化钆抑制库痞细胞(KCs),全肝照射检测其对放射诱导肝脏凋亡保护作用,研究抑制KCs对放射性肝损伤的防护作用,从非实质细胞和实质细胞相互作用全新角度探索放射性肝脏损伤RILD)的发病机制和防护策略。
材料和方法：Sprague-Dawley大鼠放疗前24小时腹腔注射三氯化钆(GdC1310 mg/kg体重)清除肝内KCs。大鼠随机分为4组：第1组假照射腹腔注射生理盐水；第2组假照射腹腔注射GdCl3;第3组腹腔注射生理盐水全肝照射；第4组腹腔注射GdCl3全肝照射。腹腔注射GdCl3后不同时间点通过KCs特异性免疫抗原CD-163(ED2)免疫组织化学染色检测肝脏KCs数量,确认GdCl3对肝内KCs细胞的抑制作用。放疗后不同时点全麻下去肝脏及血清标本,检测凋亡相关细胞因子TNF-α、IL-6及IL-1β基因和蛋白表达情况。通过肝细胞和肝内皮细胞凋亡、肝细胞微核技数评估放射诱导肝脏凋亡,进一步通过肝脏组织病理学和血清酶学改变评估肝脏损伤程度。
结果：腹腔注射GdCl3对肝脏没有明显毒副作用,CD163 (ED2)是肝内KCs细胞的标记物,GdCl3注射后门脉周围ED2阳性KCs细胞数0,2,6,24和48小时分别是正常情况下11.8%±4.5%,11.5%±2.5%,12.5%±4.2%,9.5%±4.8%和12.5%±4.1%；小叶中心区域分别为7.9%±3.1%,8.2%±3.4%,9.3%±2.4%,8.0%±1.4%和9.5%±1.9%。第3组放疗后肝内凋亡细胞开始增多,6小时肝内凋亡细胞数达到高峰,第4组凋亡细胞数在放疗后各个时间点都显著低于第3组。通过双标记技术显示放疗后6小时肝窦内皮细胞凋亡细胞,第4组显著低于第3组。微核技术是反映射线对染色体损伤简单而有效的方法,30Gy照射组肝细胞微核数达到19.8%±5.5%,GdCl 3腹腔注射后减少到7.9%±2.6%。通过肝脏酶学和组织病理学分析都同样显示GdCl3抑制KCs细胞对放射性肝损伤的显著保护作用。抑制KCs后放射性肝损伤相关的细胞因子TNF-α, IL-6及IL-1B的基因及蛋白的表达都显著抑制。
结论：选择性抑制Kupffer细胞可以显著抑制放射诱导肝脏损伤相关因子的表达减轻放射肝损伤。
Primary liver cancer (PLC) is a common malignant tumor, although radical surgical resection and liver transplantation are still the main way to cure,80%of patients missed opportunity to radical surgery after diagnosis. More and more conclusive clinical data supported that the PLC is a radiosensitive tumor. Radiaiton induced liver disease(RILD) is mainly fatal complications secondary to radiotherapy. The liver is a radiation sensitive organ in vivo similar to bone marrow, lymphoid tissues, however, hepatocytes are radiation resistance in vitro. It is difficult to explain using the "classical targeted cells theory". Previous studies have confirmed that intraheptic microenvironment, including non-parenchymal cells and released cytokines play the pivotal role in pathogenesis of RILD, which is called radiation induced non-targeted effect. Radiation-induced multiple intracellular signaling pathways activation contribute to information transfer between cells form a large regulatory networks, but the relationship between them and the control model is still unclear. Literatures support nonparenchymal cells are radiation sensitive cells and released large amounts of cytokines after radiotherapy. It has been confirmed that transforming growth factor-p (TGF-β) is closely related with the RILD, but the exact mechanism remains unclear. This study concentrated on radiation-induced non-targeted effects through inhibiting TGF-βsignaling or Kupffer cells in the pathogenesis of RILD.Try to explore the molecular mechanism and prevention strategies of RILD from a new perspective.
Part I:Construction of recombinant adenovirus carrying the human soluble TβRII-Fc fusion gene using the AdMax system
Purpose: To construct the adenovirus vector encoding the sequence of the type II TGF-βreceptor (TβRII) fused to the human immunoglobulin Fc fragment (IgFC).
Methods:Human TβRII fusion gene were amplified by reverse transcriptase -polymerase chain reaction (RT-PCR). TβRII gene was cloned into pDC316-cmv-EGFP vector. Primers designing and PCR amplification for IgFC. Ligation for the PCR product and PDC316-TPRII to obtain PDC316-TβRII-IgFC. The positive plasmids are confirmed by complete sequencing. All gene sequences were confirmed by PCR verification, restriction digestion and sequencing.The PDC316-TβRII-IgFC plasmid was cotransfected with adenoviral backbone vectors pBHGlox_E1,3Cre into 293 cells to package therecombinant adenovirus. Extracted viral genomic DNA followed PCR verification the target gene. Product and purify virion, then schizolysis the purified viruses with 10×virus lysate buffer.
Results:Recombinant adenoviral vector Ad TβRIIFC was constructed successfully, which was confirmed by restriction ellzyme digestion and GFP expression. Conclusion:The recombinant adenoviral vector carrying human TβRII-FC fusion gene was successfully constructed, and will be lay the foundation of application of gene therapy to radiation induced liver fibrosis.
Part II:Radiation-Induced Liver Fibrosis is mitigated by gene therapy inhibiting transforming Growth Factor-βSignaling in the Rat
Purpose:We determined whether anti-TGF-βintervention can halt the progression of established radiation-induced liver fibrosis.
Methods:A replication-defective adenoviral vector expressing the extracellular portion of human TβRII and the Fc portion of immunoglobulin IgG fusion protein (AdTβRIIFc) was produced. The entire liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM). Then, RILFM animals were treated with AdTβRIIFc (1×1011 PFU, TβRII), control virus (1×1011 PFU, AdGFP), or saline (SALIN). Delayed radiation liver injury was assessed by histology and immunohistochemistry. Chronic oxidative stress damage, hepatic stellate cell (HSC) activation, and hepatocyte regeneration were also analyzed.
Results:In rats infected with AdTβRIIFc, fibrosis was significantly mitigated compared with rats treated with AdGFP or saline, as assessed by histology, hydroxyproline content, and the serum level of hyaluronic acid. Compared with AdGFP rats, AdTβRIIFc-treated rats exhibited decreased oxidative stress damage and HSC activation, and preserved liver function.
Conclusions:Our results demonstrate that TGF-βplays a critical role in the progression of liver fibrosis and suggest that anti-TGF-βintervention is feasible and ameliorates established fibrotic livers. In addition, chronic oxidative stress may be involved in the progression of RILF.
Part III:Inactivation of kupffer cells by Gadolinium Chloride protects murine liver from radiation-induced apoptosis.
Purpose:To determine whether the inhibition of Kupffer cells before radiotherapy (RT) would protect hepatocytesfrom radiation-induced apoptosis.
Materials and Methods:A single 30-Gy fraction was administered to the upper abdomen of Sprague-Dawley rats.The Kupffer cell inhibitor gadolinium chloride (GdC13; 10 mg/kg body weight) was intravenously injected 24 h before RT. The rats were divided into four groups:group 1, sham RT plus saline (control group); group 2, sham RT plus GdC13; group 3, RT plus saline; and group 4, RT plus GdC13. Liver tissue was collected for measurementof apoptoic cytokine expression and evaluation of radiation-induced liver toxicity by analysis of liver enzyme activities, hepatocyte micronucleus formation, apoptosis, and histologic staining.
Results:The expression of interleukin-lb, interleukin-6, and tumor necrosis factor-a was significantly attenuated in group 4 compared with group 3 at 2,6,24, and 48 h after injection (p<0.05). At early points after RT, the rats in group 4 exhibited significantly lower levels of liver enzyme activity, apoptotic response, and hepatocyte micronucleus formation compared with those in group 3.
Conclusion:Selective inactivation of Kupffer cells with GdC13 reduced radiation-induced cytokine production andprotected the liver against acute radiation-induced damage.
第一部分应用AdMax系统构建TβIIR-IgFc融合基因重组腺病毒
目的：应用AdMax系统构建携带Ⅱ型TGFβ受体(TβIIR)IgFc融合基因重组腺病毒,为进一步研究放射性肝纤维化干预打下基础。
材料和方法：针对TβIIR设计引物,PCR目的基因TβI IR构建PDC316-TβIIR:针对工gFc设计引物,PCR目的基因IgFc,连入PDC316-T p IIR构建PDC316-TβIIR-IgFc；双质粒共转染293细胞,同源重组产生重组腺病毒,AdMax腺病毒包装系统由骨架质粒：pBHGl ox-E1,3Cre和穿梭质粒：pDC316-2501组成。使用LipOfectam lne2000法转染293细胞包装携带目的融合基因的重组腺病毒,少量提取重组腺病毒DNA检测证实为复制缺陷型TβIIR-IgFc基因重组腺病毒后大量扩增、生产、纯化及鉴定。
结果：PCR扩增TβRII基因,酶切连接到pDC316-cmv-EGFP空载体,提取质粒酶切鉴定电泳检测正确；PCR扩增IgFC基因,酶切、连接PDC316-TβRII载体,再提取质粒,根据PDC316载体序列设计引物,PCR琼脂糖凝胶电泳与预期的目的基因片段一致,测序鉴定正确。双质粒共转染293细胞,转染后第9天出毒而在光学显微镜下观察出毒现象表现为细胞变大变圆,呈“葡萄串”样形态学特征,并开始出现明显噬斑。转染后第14天待细胞大部分病变并从底部脱落进行收毒,证明有感染能力病毒颗粒包装成功。重组腺病毒经RT-PCR扩增后,产物电泳观察出现一条特异性预期条带,证明该重组腺病毒携带目的基因。测得扩增后病毒滴度为2.6×1012pfu／m1。
结论：应用AdMax系统可方便、快捷地构建携带目融合基因的复制缺陷型重组腺病毒。
第二部分抑制TGF-β信号转导通路有效减轻大鼠放射性肝纤维化
目的：本研究拟通过携带可溶性TβIIR的复制缺陷性重组腺病毒(AdTβRIIFc)选择性阻断TGF-β信号转导通路治疗晚期放射性损伤,明确TGF-β在放射性肝纤维化(RILF)发展中作用机制,进一步探索RILF的治疗策略。
方法：RILF大鼠模型采用上腹部全肝30Gy单次照射,放疗后活过6个月的大鼠肝脏都出现晚期纤维化表现。随机分成4组,第1组模型组(RILFM);第2组携带目的基因重组腺病毒基因治疗组：腹腔注射1X1011 PFU AdTβRIIFc;第3组空病毒对照组,腹腔注射相同剂量和滴度的对照病毒；第4组生理盐水对照组,腹腔注射等体积的生理盐水(SALINE).
结果：抑制TGF-β信号转导通路有效抑制放射性诱导肝星状细胞(HSC)活化、胶原蛋白-1(Col-I)和纤维粘连接蛋白(Fibronectin, FN)表达；阻断TGF-β信号转导通路可以减轻RILF阶段慢性氧化应急(Chronic Oxidative Stress, COS) DNA损伤。另外,抗TGF-β治疗可以有效释放TGF-β对肝细胞生长抑制效应,提高肝细胞代偿能力,有效缓解RILF对肝脏功能损伤。
结论：TGF-β信号转导通路在RILF的形成和发展中发挥重要作用,阻断TGF-β信号转导通路有效缓解RILF。
第三部分抑制肝脏Kupffer细胞减轻放射诱导肝脏细胞凋亡
目的：通过放疗前三氯化钆抑制库痞细胞(KCs),全肝照射检测其对放射诱导肝脏凋亡保护作用,研究抑制KCs对放射性肝损伤的防护作用,从非实质细胞和实质细胞相互作用全新角度探索放射性肝脏损伤RILD)的发病机制和防护策略。
材料和方法：Sprague-Dawley大鼠放疗前24小时腹腔注射三氯化钆(GdC1310 mg/kg体重)清除肝内KCs。大鼠随机分为4组：第1组假照射腹腔注射生理盐水；第2组假照射腹腔注射GdCl3;第3组腹腔注射生理盐水全肝照射；第4组腹腔注射GdCl3全肝照射。腹腔注射GdCl3后不同时间点通过KCs特异性免疫抗原CD-163(ED2)免疫组织化学染色检测肝脏KCs数量,确认GdCl3对肝内KCs细胞的抑制作用。放疗后不同时点全麻下去肝脏及血清标本,检测凋亡相关细胞因子TNF-α、IL-6及IL-1β基因和蛋白表达情况。通过肝细胞和肝内皮细胞凋亡、肝细胞微核技数评估放射诱导肝脏凋亡,进一步通过肝脏组织病理学和血清酶学改变评估肝脏损伤程度。
结果：腹腔注射GdCl3对肝脏没有明显毒副作用,CD163 (ED2)是肝内KCs细胞的标记物,GdCl3注射后门脉周围ED2阳性KCs细胞数0,2,6,24和48小时分别是正常情况下11.8%±4.5%,11.5%±2.5%,12.5%±4.2%,9.5%±4.8%和12.5%±4.1%；小叶中心区域分别为7.9%±3.1%,8.2%±3.4%,9.3%±2.4%,8.0%±1.4%和9.5%±1.9%。第3组放疗后肝内凋亡细胞开始增多,6小时肝内凋亡细胞数达到高峰,第4组凋亡细胞数在放疗后各个时间点都显著低于第3组。通过双标记技术显示放疗后6小时肝窦内皮细胞凋亡细胞,第4组显著低于第3组。微核技术是反映射线对染色体损伤简单而有效的方法,30Gy照射组肝细胞微核数达到19.8%±5.5%,GdCl 3腹腔注射后减少到7.9%±2.6%。通过肝脏酶学和组织病理学分析都同样显示GdCl3抑制KCs细胞对放射性肝损伤的显著保护作用。抑制KCs后放射性肝损伤相关的细胞因子TNF-α, IL-6及IL-1B的基因及蛋白的表达都显著抑制。
结论：选择性抑制Kupffer细胞可以显著抑制放射诱导肝脏损伤相关因子的表达减轻放射肝损伤。
Primary liver cancer (PLC) is a common malignant tumor, although radical surgical resection and liver transplantation are still the main way to cure,80%of patients missed opportunity to radical surgery after diagnosis. More and more conclusive clinical data supported that the PLC is a radiosensitive tumor. Radiaiton induced liver disease(RILD) is mainly fatal complications secondary to radiotherapy. The liver is a radiation sensitive organ in vivo similar to bone marrow, lymphoid tissues, however, hepatocytes are radiation resistance in vitro. It is difficult to explain using the "classical targeted cells theory". Previous studies have confirmed that intraheptic microenvironment, including non-parenchymal cells and released cytokines play the pivotal role in pathogenesis of RILD, which is called radiation induced non-targeted effect. Radiation-induced multiple intracellular signaling pathways activation contribute to information transfer between cells form a large regulatory networks, but the relationship between them and the control model is still unclear. Literatures support nonparenchymal cells are radiation sensitive cells and released large amounts of cytokines after radiotherapy. It has been confirmed that transforming growth factor-p (TGF-β) is closely related with the RILD, but the exact mechanism remains unclear. This study concentrated on radiation-induced non-targeted effects through inhibiting TGF-βsignaling or Kupffer cells in the pathogenesis of RILD.Try to explore the molecular mechanism and prevention strategies of RILD from a new perspective.
Part I:Construction of recombinant adenovirus carrying the human soluble TβRII-Fc fusion gene using the AdMax system
Purpose: To construct the adenovirus vector encoding the sequence of the type II TGF-βreceptor (TβRII) fused to the human immunoglobulin Fc fragment (IgFC).
Methods:Human TβRII fusion gene were amplified by reverse transcriptase -polymerase chain reaction (RT-PCR). TβRII gene was cloned into pDC316-cmv-EGFP vector. Primers designing and PCR amplification for IgFC. Ligation for the PCR product and PDC316-TPRII to obtain PDC316-TβRII-IgFC. The positive plasmids are confirmed by complete sequencing. All gene sequences were confirmed by PCR verification, restriction digestion and sequencing.The PDC316-TβRII-IgFC plasmid was cotransfected with adenoviral backbone vectors pBHGlox_E1,3Cre into 293 cells to package therecombinant adenovirus. Extracted viral genomic DNA followed PCR verification the target gene. Product and purify virion, then schizolysis the purified viruses with 10×virus lysate buffer.
Results:Recombinant adenoviral vector Ad TβRIIFC was constructed successfully, which was confirmed by restriction ellzyme digestion and GFP expression. Conclusion:The recombinant adenoviral vector carrying human TβRII-FC fusion gene was successfully constructed, and will be lay the foundation of application of gene therapy to radiation induced liver fibrosis.
Part II:Radiation-Induced Liver Fibrosis is mitigated by gene therapy inhibiting transforming Growth Factor-βSignaling in the Rat
Purpose:We determined whether anti-TGF-βintervention can halt the progression of established radiation-induced liver fibrosis.
Methods:A replication-defective adenoviral vector expressing the extracellular portion of human TβRII and the Fc portion of immunoglobulin IgG fusion protein (AdTβRIIFc) was produced. The entire liver was exposed to 30 Gy irradiation to generate a RILF model (RILFM). Then, RILFM animals were treated with AdTβRIIFc (1×1011 PFU, TβRII), control virus (1×1011 PFU, AdGFP), or saline (SALIN). Delayed radiation liver injury was assessed by histology and immunohistochemistry. Chronic oxidative stress damage, hepatic stellate cell (HSC) activation, and hepatocyte regeneration were also analyzed.
Results:In rats infected with AdTβRIIFc, fibrosis was significantly mitigated compared with rats treated with AdGFP or saline, as assessed by histology, hydroxyproline content, and the serum level of hyaluronic acid. Compared with AdGFP rats, AdTβRIIFc-treated rats exhibited decreased oxidative stress damage and HSC activation, and preserved liver function.
Conclusions:Our results demonstrate that TGF-βplays a critical role in the progression of liver fibrosis and suggest that anti-TGF-βintervention is feasible and ameliorates established fibrotic livers. In addition, chronic oxidative stress may be involved in the progression of RILF.
Part III:Inactivation of kupffer cells by Gadolinium Chloride protects murine liver from radiation-induced apoptosis.
Purpose:To determine whether the inhibition of Kupffer cells before radiotherapy (RT) would protect hepatocytesfrom radiation-induced apoptosis.
Materials and Methods:A single 30-Gy fraction was administered to the upper abdomen of Sprague-Dawley rats.The Kupffer cell inhibitor gadolinium chloride (GdC13; 10 mg/kg body weight) was intravenously injected 24 h before RT. The rats were divided into four groups:group 1, sham RT plus saline (control group); group 2, sham RT plus GdC13; group 3, RT plus saline; and group 4, RT plus GdC13. Liver tissue was collected for measurementof apoptoic cytokine expression and evaluation of radiation-induced liver toxicity by analysis of liver enzyme activities, hepatocyte micronucleus formation, apoptosis, and histologic staining.
Results:The expression of interleukin-lb, interleukin-6, and tumor necrosis factor-a was significantly attenuated in group 4 compared with group 3 at 2,6,24, and 48 h after injection (p<0.05). At early points after RT, the rats in group 4 exhibited significantly lower levels of liver enzyme activity, apoptotic response, and hepatocyte micronucleus formation compared with those in group 3.
Conclusion:Selective inactivation of Kupffer cells with GdC13 reduced radiation-induced cytokine production andprotected the liver against acute radiation-induced damage.
引文
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