TGF-beta,radiation-induced pulmonary injury and lung cancer

Purpose : To determine whether changes in TGF-beta plasma levels during radiation therapy may be useful in predicting radiation-induced pulmonary injury and tumour response in non-small-cell lung cancer (NSCLC) patients. Materials and methods : Plasma TGF-beta was investigated in 27 patients with stage III NSCLC, who were treated with 60 Gy (2Gy/day) radiotherapy with or without carboplatin. TGF-beta was measured prior to beginning radiotherapy and weekly during treatment; evaluated as a ratio between TGF-beta levels obtained during treatment and the pretreatment TGF-beta level. The endpoints of the study were development of symptomatic radiation pneumonitis and tumour response. Results : Nine of the 27 patients developed pneumonitis. The patients who developed pneumonitis had high persistent TGF-beta levels throughout the course of treatment (TGF-beta ratio>1), whereas the TGF-beta levels in patients who did not develop pneumonitis were unchanged or declined towards normal (TGF-beta ratio<1). Patients who responded to treatment had low or normal TGF-beta levels during treatment compared with patients who failed to respond. Other parameters such as pretreatment TGF-beta values, carboplatin treatment or field size did not appear to have a significant effect, which is probably due to the small number of patients entered in the study. Conclusion : This pilot study, with a limited number of patients, suggests the hypothesis that elevated TGF-beta levels during radiotherapy may not only indicate patients with a higher risk of developing pulmonary toxicity but also patients with a higher risk of treatment failure. This remains to be tested in a larger clinical study.     

Treg与放射性肺损伤

放射性肺损伤（RILI）是胸部肿瘤放疗后常见的不良反应之一,在数月后往往发展成为放射性肺纤维化。近年来,研究者对RILI的发生发展机制开展了大量探索,其中调节性T细胞（Treg）在RILI进展中的免疫学机制尤其受到国内外学者的重视。本期重点号刊登了几篇Treg与RILI方面的文章,这些文章从Treg在肺组织内的数量改变和免疫调节机制等方面报道了Treg参与RILI发生发展的研究成果,为RILI的预防和治疗提供了重要的科学基础。     

肺功能分析在放射性肺损伤防治药物药效评价中的作用

目的：探讨肺功能分析在放射性肺损伤防治药物药效研究中的意义。方法采用30只C57BL／6小鼠以20 Gy的X线行小鼠胸部单次照射,照射后给予地塞米松[给药组按4．5 mg／（ kg· d）的剂量给予地塞米松磷酸钠注射液,2周后减半维持至1个月],对照组和模型组给予等体积生理盐水。照射后1个月,使用EMKA肺功能分析系统在清醒状态下行肺功能测试,随后活杀取材,HE染色观察肺组织结构变化,应用Image-pro图像分析软件分析肺泡腔面积。结果给药1个月后,模型组及地塞米松组小鼠肺功能部分指标,如50％呼气流量、每分通气量、呼气峰值、吸气峰值、潮气量较对照组明显降低,但地塞米松组较模型组降低程度有所减轻。肺组织病理变化示,地塞米松组小鼠肺泡腔面积减小程度、肺间质中性粒细胞浸润程度均较模型组有所减轻,与肺功能分析结果相符。结论地塞米松对放射性肺损伤具有一定治疗效果;肺功能分析与肺组织病理变化相结合印证,可以有效评价放射性肺损伤防治药物的药效。     

Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury

PURPOSE: Remodeling of extracellular matrix (ECM) after lung damage depends on collagen degrading Matrix-Metallo-Proteinases (MMP) and their endogenous inhibitors (Tissue-Inhibitors of Metallo-Proteinases, TIMP). Transforming growth factor (TGF)-beta1 has been implicated in the pathogenesis of radiation-induced lung fibrosis upon its effects on fibroblast proliferation and collagen synthesis. Lung cancer patients have often elevated TGF-beta1 plasma levels as a result of increased TGF-beta1 expression in their tumours. On this background, we investigated the effect of irradiation on the MMP/TIMP system in the lung tissue of normal and transgenic TGF-beta1 mice, in which TGF-beta1 is overexpressed in the liver resulting in high TGF-beta1 plasma levels. MATERIAL AND METHODS: Transgenic (TG) and wild-type (WT) mice underwent thoracic irradiation with 12 Gy or sham-irradiation. For each study group (TG 12 Gy; TG 0 Gy; WT 12 Gy; WT 0 Gy) 8 mice were sacrificed at 4 and 8 weeks after (sham-) irradiation. The TGF-beta1, TIMP-1/-2/-3 expression in the lung tissue was quantified by Western blot; the MMP-2 and MMP-9 activity was analysed by zymography. The cellular origin of the MMP and TIMP was localised by immunohistochemistry. RESULTS: Irradiation had no influence on the TIMP-1/-2/-3, but increased significantly the MMP-2 /-9 expression. In the lung tissue of TG mice the TIMP-1/-2/-3 expression was elevated, the MMP-9 activity was decreased. The immunhistochemical study showed that parenchymal and inflammatory cells express these MMP/TIMP. CONCLUSION: Our results provide evidence that the overexpression of MMP-2 and MMP-9 is involved in the inflammatory response of radiation-induced lung injury. MMP-2 and MMP-9 are known to degrade collagen IV of basement membranes, therefore affecting the structural integrity of lung tissue. In contrast, in lung tissue of TG mice the TIMP-1/-2/-3 expression was up-regulated and the MMP-9 activity was diminished, thereby decreasing possibly the ECM degradation leading to lung fibrosis.     

Matrix-Metallo-Proteinases and their tissue inhibitors in radiation-induced lung injury

Purpose: Remodeling of extracellular matrix (ECM) after lung damage depends on collagen degrading Matrix-Metallo-Proteinases (MMP) and their endogenous inhibitors (Tissue-Inhibitors of Metallo-Proteinases, TIMP). Transforming growth factor (TGF)-β1 has been implicated in the pathogenesis of radiation-induced lung fibrosis upon its effects on fibroblast proliferation and collagen synthesis. Lung cancer patients have often elevated TGF-β1 plasma levels as a result of increased TGF-β1 expression in their tumours. On this background, we investigated the effect of irradiation on the MMP/TIMP system in the lung tissue of normal and transgenic TGF-β1 mice, in which TGF-β1 is overexpressed in the liver resulting in high TGF-β1 plasma levels.

Material and methods: Transgenic (TG) and wild-type (WT) mice underwent thoracic irradiation with 12 Gy or sham-irradiation. For each study group (TG 12 Gy; TG 0 Gy; WT 12 Gy; WT 0 Gy) 8 mice were sacrificed at 4 and 8 weeks after (sham-) irradiation. The TGF-β1, TIMP-1/-2/-3 expression in the lung tissue was quantified by Western blot; the MMP-2 and MMP-9 activity was analysed by zymography. The cellular origin of the MMP and TIMP was localised by immunohistochemistry.

Results: Irradiation had no influence on the TIMP-1/-2/-3, but increased significantly the MMP-2 /-9 expression. In the lung tissue of TG mice the TIMP-1/-2/-3 expression was elevated, the MMP-9 activity was decreased. The immunhistochemical study showed that parenchymal and inflammatory cells express these MMP/TIMP.

Conclusion: Our results provide evidence that the overexpression of MMP-2 and MMP-9 is involved in the inflammatory response of radiation-induced lung injury. MMP-2 and MMP-9 are known to degrade collagen IV of basement membranes, therefore affecting the structural integrity of lung tissue. In contrast, in lung tissue of TG mice the TIMP-1/-2/-3 expression was up-regulated and the MMP-9 activity was diminished, thereby decreasing possibly the ECM degradation leading to lung fibrosis.     

Treg分化对放射性肺损伤的影响

目的 探讨调节性T细胞（Treg）的分化对放射性肺损伤的影响及其作用机制。 方法 建立Treg抑制小鼠模型,按随机数字表法将C57BL/6小鼠分成4组：空白对照组、单纯照射组、照射+免疫球蛋白G（IgG）组和照射+CD25组,每组12只,除空白对照组外其余3组小鼠给予单次20 Gy X射线全胸照射,照射+IgG组和照射+CD25组小鼠每周腹腔注射IgG抗体和CD25抗体。分别于照射后第4周和第8周各处死小鼠6只,采用流式细胞术检测小鼠肺组织内CD25+Foxp3+Treg（Foxp3：叉头样转录因子3）的百分比以鉴定模型是否建立成功;采用Western blot法检测单纯照射组小鼠肺组织内神经纤毛蛋白1（NRP1）的表达;采用免疫荧光法检测每组小鼠肺组织内CD25+NRP1+Treg的百分比;拍照并观察每组小鼠皮肤的损伤情况,采用苏木精-伊红染色法检测小鼠肺组织的病理学改变;采用酶联免疫吸附测定法检测每组小鼠肺组织内转化生长因子β1（TGF-β1）、白细胞介素（IL）-17A、干扰素γ（IFN-γ）、IL-2和IL-4的水平变化。两组间比较采用独立样本t检验。 结果 流式细胞术检测结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内CD25+Foxp3+Treg百分比[（1.73±0.04）%、（2.13±0.15）%]均较空白对照组[（1.14±0.02）%、（1.70±0.06）%] 明显升高,差异均有统计学意义（t=−26.680、−4.545,P=0.000、0.010）,抑制Treg后,第4周和第8周时照射+CD25组小鼠肺组织内CD25+Foxp3+Treg百分比[（0.72±0.14）%、（0.27±0.02）%]均较单纯照射组明显降低,差异均有统计学意义（t=5.296、37.538,均P=0.000）。Western blot结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内NRP1蛋白表达水平均较空白对照组升高,差异均有统计学意义（t=−7.341、−9.127,均P=0.000）。免疫荧光法检测结果显示,照射后第4周和第8周,单纯照射组小鼠肺组织内CD25+NRP1+Treg的百分比均较空白对照组升高,而照射+CD25组CD25+NRP1+Treg百分比均较单纯照射组降低,且差异均有统计学意义（t=8.926、14.457,P=0.001、0.000）。观察小鼠皮肤损伤程度后发现,照射后第4周和第8周,单纯照射组小鼠皮肤损伤严重,而照射+CD25组小鼠照射后第4周时皮肤基本完好,第8周时出现脱毛脱皮。病理学结果显示,照射后第4周和第8周,与空白对照组相比,单纯照射组小鼠的肺组织结构破坏,肺泡壁增厚,细胞外基质增多,而照射+CD25组小鼠的肺组织结构完整,肺泡壁纤细。酶联免疫吸附测定结果显示,与空白对照组相比,照射后第4周,单纯照射组小鼠肺组织内IL-17A和IL-4的水平均升高,差异均有统计学意义（t=−8.492、−15.796,P=0.001、0.000）,照射后第8周,TGF-β1和IL-17A水平升高,差异均有统计学意义（t=−11.072、−7.167,P=0.000、0.002）,IL-2水平在第4周和第8周时均降低,IFN-γ水平在第4周时升高,差异有统计学意义（t=−27.393,P=0.000）,第8周时下降;与单纯照射组相比,照射+CD25组小鼠TGF-β1和IL-17A水平在第4周和第8周时均降低（t=6.037、4.524、5.496、4.772,均P=0.000）,IFN-γ水平升高（t=−7.006、−12.565,P=0.002、0.000）,差异均有统计学意义,而IL-2和IL-4水平在第4周时均降低,第8周时均明显升高,差异均有统计学意义（t=2.866、−9.090、8.833、−7.191,均P=0.000）。 结论 放射性肺损伤小鼠的肺组织中出现Treg分化,并增强分泌TGF-β1促炎因子,同时干扰辅助T细胞（Th1、Th2型）细胞因子的平衡来促进放射性肺损伤的发生。     

獐牙菜苦苷对放射性肺损伤的防护作用

目的 探讨獐牙菜苦苷对电离辐射所致肺损伤的防护作用和机制。方法 实验将人支气管上皮细胞(Beas-2B)和人胚肺成纤维细胞(HELF)分为对照组、10 Gy X射线照射组、照射+獐牙菜苦苷组,检测獐牙菜苦苷对 X射线照射后的影响。检测射线暴露后细胞的乳酸脱氢酶(LDH)释放量、细胞的增殖情况、DNA损伤水平、活性氧(ROS)水平、脂质过氧化物水平、铁离子水平、铁死亡相关蛋白SLC7A11(xCT)及谷胱甘肽过氧化物酶(GPX4)含量变化。为了验证獐牙菜苦苷在体内对放射性肺损伤是否具有防护作用,建立放射性肺损伤小鼠模型,将C57BL/6J雄性小鼠分为对照组、照射组、照射+獐牙菜苦苷组,每组5只,对小鼠胸部进行15 Gy X射线照射,照射后30 d收集小鼠肺组织及血清。观察受照小鼠肺组织病理变化、肺组织氧化应激水平及肺组织中γ-H2AX、GPX4含量变化和炎性因子水平变化。结果 与照射组相比,照射+獐牙菜苦苷组(130 μmol/l)细胞的增殖率及克隆形成率明显上升(Beas-2B:t=5.50~5.92,P＜0.05;HELF:t=3.79~5.51,P＜0.05);LDH释放率、ROS含量、脂质过氧化物水平及铁离子含量显著降低(Beas-2B:t=3.00~16.99,P＜0.05;HELF:t=4.10~10.97,P＜0.05)。DNA损伤水平显著下降(Beas-2B:t=5.69~8.27,P＜0.05;HELF:t=3.44~14.77,P＜0.05)。xCT和GPX4蛋白表达发生上调(Beas-2B:t=2.90~3.27,P＜0.05;HELF:t=3.01~7.07,P＜0.05)。体内实验中,与照射组相比,獐牙菜苦苷预处理可有效提升小鼠肺组织中GSH和GPX4含量(t=2.31~2.65,P＜0.05),降低MDA和γ-H2AX含量(t=2.71~4.19,P＜0.05),同时降低小鼠血清中IL-6及IL-1β水平(t=3.16~4.56,P＜0.05)。结论 獐牙菜苦苷可以通过降低电离辐射诱导的DNA损伤和氧化应激水平,从而对电离辐射引起的肺损伤发挥防护作用,为研发新型放射性肺损伤防护剂提供思路。     

穿心莲内酯对小鼠放射性肺损伤的防护作用

目的 观察穿心莲内酯对C57BL/6小鼠放射性肺损伤的保护效应。方法 将80只C57BL小鼠完全随机分为0.9% 氯化钠溶液组（空白对照组）、穿心莲内酯组（单纯给药组）、放射+0.9%氯化钠溶液组（单纯照射组）和放射+穿心莲内酯组（联合组）,每组20只。照射前单纯给药组和联合组用穿心莲内酯 20 mg·kg^-1·d^-1灌胃,空白对照组和单纯照射组用等体积0.9%氯化钠溶液灌胃,连续灌胃30 d。采用6 MV高能X射线直线加速器单次15 Gy照射,建立小鼠全肺放射性肺损伤模型。取小鼠肺组织HE染色、Masson染色进行组织病理学观察;采用 ELISA 法检测小鼠血清转化生长因子β1（TGF-β1）、肿瘤坏死因子α（TNF-α）;紫外分光光度计检测肺组织丙二醛（MDA）含量、超氧化物歧化酶（SOD）活力和羟脯氨酸（Hyp）含量。结果 联合组小鼠肺组织损伤程度较单纯照射组小鼠明显减轻,其肺系数、肺组织MDA含量、羟脯氨酸含量以及血清 TGF-β1、TNF-α表达水平虽然略高于空白对照组,但低于单纯照射组差异有统计学意义（t_肺系数=1,60, t_MDA=7.06, t_羟脯氨酸=17.44, t_TGF-β1=16.67, t _TNF-α=14.03,P <0.05）;联合组小鼠血清SOD活力明显高于单纯照射组（t=60.81,P<0.05）,但低于空白对照组和单纯给药组;单纯给药组小鼠各项检测指标与空白对照组相比,差异均无统计学意义。结论 穿心莲内酯可有效减轻小鼠的放射性肺损伤,且对小鼠肺组织无明显毒性。     

小鼠放射性肺损伤模型的建立与鉴定

目的建立小鼠放射性肺损伤模型。方法雌性C57BL/6小鼠90只,随机分作2组:(1)对照组(36只)不做任何处理;(2)照射组(54只)全肺单次照射12Gy。于照射后1、24、72h和1、2、4、8、16、24周,取照射组及相同鼠龄对照组小鼠肺组织,分别用HE、Masson染色在光镜下观察组织病理改变和胶原纤维沉积,免疫组织化学法来观察肺组织基底膜连续性和肺泡表面活性物质的表达。用碱水解法来测定羟脯氨酸含量。结果与对照组比较,照射组小鼠的肺组织在照射后存在明显的病理组织学上的改变,早期以急性炎症反应为主,表现为肺充血、水肿、肺间质增厚,后期肺损伤以肺泡间隔的进行性纤维化为特征;免疫组织化学法的结果也进一步证实了病理组织学改变,与对照组相比,照射组小鼠的肺组织的基底膜连续性中断,并且肺泡表面活性物质的表达明显增多;同时,对照组湿肺羟脯氨酸含量为(0·763±0·029)μg/mg,照射组湿肺羟脯氨酸含量(0·875±0·009)μg/mg明显增高(P<0·05)。结论该模型较好地模拟了放射性肺损伤的发生和发展过程,为今后进一步研究放射性肺损伤发生的机制提供了实验基础。     

Mitigation of radiation-induced lung injury by genistein and EUK-207

Purpose:?We examined the effects of genistein and/or Eukarion (EUK)-207 on radiation-induced lung damage and investigated whether treatment for 0–14 weeks (wks) post-irradiation (PI) would mitigate late lung injury.

Materials and methods:?The lungs of female Sprague-Dawley (SD) rats were irradiated with 10 Gy. EUK-207 was delivered by infusion and genistein was delivered as a dietary supplement starting immediately after irradiation (post irradiation [PI]) and continuing until 14 wks PI. Rats were sacrificed at 0, 4, 8, 14 and 28 wks PI. Breathing rate was monitored and lung fibrosis assessed by lung hydroxyproline content at 28 wks. DNA damage was assessed by micronucleus (MN) assay and 8-hydroxy-2-deoxyguanosine (8-OHdG) levels. The expression of the cytokines Interleukin (IL)-1α, IL-1β, IL-6, Tumor necrosis factor (TNF)-α and Transforming growth factor (TGF)-β1, and macrophage activation were analyzed by immunohistochemistry.

Results:?Increases in breathing rate observed in the irradiated rats were significantly reduced by both drug treatments during the pneumonitis phase and the later fibrosis phase. The drug treatments decreased micronuclei (MN) formation from 4–14 wks but by 28 wks the MN levels had increased again. The 8-OHdG levels were lower in the drug treated animals at all time points. Hydroxyproline content and levels of activated macrophages were decreased at 28 wks in all drug treated rats. The treatments had limited effects on the expression of the cytokines.

Conclusion:?Genistein and EUK-207 can provide partial mitigation of radiation-induced lung damage out to at least 28 wks PI even after cessation of treatment at 14 wks PI.     

兔放射性肺损伤模型的建立及鉴定

目的 建立适合放射性肺损伤(RILI)CT灌注成像研究的兔动物模型。方法 健康新西兰大白兔48只,随机分为对照组(12只,做单肺假性照射)和实验组(36只,高能X射线单侧肺单次照射25 Gy),分别于照射后第1、6、12、24、48和72小时及第1、2、4、8、16和24周被处死,取两肺中带上、中、下野6处标本,分别进行HE染色光镜、电镜和局部肺组织TNF-α和TGF-β₁的检测。结果 实验组所有兔受照射肺均产生了RILI,早期以急性炎性反应为主,晚期以进行性肺纤维化为特征。实验组受照射1 h后局部肺组织TNF-α表达、72 h后TGF-β₁表达与对照组差异均有统计学意义(t=3.04~14.95,P＜0.05)。光镜下,实验组受照射12 h后肺泡壁厚度、6 h后肺间质面积密度、24 h后间质内纤维母细胞和纤维细胞数量与对照组差异均有统计学意义(t=4.44~39.78,P＜0.05),并分别与照射后的时间直线相关(r=0.82、0.87、0.68)。电镜下,实验组各时间点之间胶原纤维相对含量差异有统计学意义(F=100.31,P=0.000),对照组各时间点之间的差异无统计学意义。实验组受照射72 h后肺内胶原纤维相对含量与对照组差异均有统计学意义(t=3.07~45.18,P＜0.05),并与照射后时间直线相关(r=0.99)。结论 25 Gy单肺单次高能X射线照射能制作稳定、可靠的兔RILI模型,较好地模拟了RILI的发生、发展的演变过程。      

放射性肺损伤防治措施研究进展

放射性肺损伤是核辐射事故、骨髓移植预处理及胸部肿瘤放疗常见的并发症。糖皮质激素常被用于减轻放射性肺损伤的症状,但疗效并不理想。许多学者致力于评估一些防治措施在减轻辐射所致动物和人肺损伤的作用。本文就其研究进展进行综述,以期阐明防治现状,并在一定程度上对临床有所帮助。     

氧化应激在放射性肺损伤中的相关研究进展

放射治疗是胸部恶性肿瘤的重要治疗手段。放射性肺损伤是胸部放疗的主要剂量限制因素。射线作用于机体产生大量内源性和外源性活性氧/氮类物质。这些物质通过对DNA、蛋白质及脂膜的直接作用使细胞结构破坏,功能缺失,是早期肺损伤的重要原因。此外,通过一系列细胞、细胞因子的作用,慢性氧化应激逐渐形成,参与细胞通透性增加、组织水肿、细胞外基质纤维蛋白堆积的过程,最终导致放射性纤维化。氧化应激学说为人们更深入地认识放射性肺损伤提供了新的线索和途径,一些抗氧化应激药物也显示了良好的临床应用前景。     

肺癌适形放疗后放射性肺损伤CT分级的危险因素研究

目的 探讨接受三维适形放疗(3DCRT)后影响严重放射性肺损伤CT分级的危险因素。方法 回顾性分析89例3DCRT的肺癌患者临床资料和随访CT影像资料,统计各临床因素及剂量体积参数。观察放疗结束6～12个月的CT影像资料并根据CT影像资料对放射性肺损伤进行评定分级。分析≥3级严重放射性肺损伤的危险因素。统计采用SPSS15.0软件。结果 89例患者放射性肺损伤CT分级情况:0级8例占9.0%,1级13例占14.6%,2级24例占27.0%,3级23例占25.8%,4级21例占23.6%。单因素分析显示同步化疗(CCT)、大体肿瘤体积(GTV)外放边界、患侧肺平均剂量、患侧肺的V₁₅～V₄₅差异有统计学意义。多因素Logistic回归分析显示:CCT、GTV外放边界和患侧肺V₂₀是影响严重放射性肺损伤CT分级的独立危险因素。结论 对接受3DCRT的肺癌患者,CCT、GTV外放边界和患侧肺V₂₀是影响严重放射性肺损伤CT分级的临床和剂量学危险因素。     

CT appearance of acute radiation-induced injury in the lung

To determine how soon radiation-induced lung injury is detectable, to compare the CT findings with those on chest radiographs, and to observe the appearance of the abnormality during the acute phase, we performed 83 CT studies in 17 radiotherapy patients at relatively short intervals. All 17 patients received fractionated radiotherapy to the thorax with a large irradiated lung volume. The CT findings were variable; pulmonary infiltrates were homogeneous, patchy, or discrete. CT abnormalities were evident in 15 of 17 cases within 16 weeks after radiotherapy; in 13 of these it was detected within 4 weeks. In three of these 15 cases, no abnormality was detected on chest radiographs, and in three other cases, the change was observed much later on chest radiographs than on CT scans. In the other nine cases, abnormalities were detected simultaneously on CT scans and chest radiographs. In four cases, extensive radiation pneumonitis was observed on CT, but in two of these, the change was misdiagnosed on the chest radiograph. We conclude that CT is useful in the detection of acute radiation-induced pulmonary disease.     

TGF-beta1-mediated alterations of rat lung fibroblast differentiation resulting in the radiation-induced fibrotic phenotype

Purpose : To study the influence of TGF-beta1 and TGF-beta-neutralizing antibodies on the clonogenic activity and terminal differentiation of rat lung fibroblasts following radiation exposure. Material and methods : Early passage rat lung fibroblasts were used in this study. Colony formation assays were applied to determine the radiation sensitivity as well as radiation-induced alterations in differentiation pattern. Based on a TGF-beta1-specific ELISA system, the amount of TGF-beta1 in the culture medium of sham-irradiated and irradiated cultures was determined. Results : Applying immediate (ip) and delayed plating (dp) procedures for cells irradiated in the subconfluent state, distinct differences in the radiation dose–response curves could be observed (SF2 ip 0.20 +/- 0.025 versus SF2 dp 0.51 +/- 0.0077). Upon irradiation with a single dose of 4 Gy the level of TGF-beta1 found in the culture medium increased by about 60%. Radiation-induced terminal differentiation of progenitor fibroblasts (MF) to postmitotic fibrocytes (PMF) was expressed by the change of the ratio of PMF:MF (0.8 at 0 Gy versus 3.0 at 4 Gy). Neutralizing antibodies directed against TGF-beta inhibited both the radiation-induced reduction in clonogenic activity of rat lung fibroblasts as well as the radiation-induced terminal differentiation of MF progenitor fibroblasts to PMF postmitotic fibrocytes. Conclusion : The results indicate the important role of TGF-beta1 in triggering radiation-induced inhibition of clonogenic activity as well as terminal differentiation of rat lung fibroblasts. The data presented support the hypothesis that terminal differentiation is an essential cellular process in the development of radiation-induced fibrosis in the lung.     

消旋山莨菪碱减轻小鼠放射性肺损伤的作用及分子机制研究

目的 探讨消旋山莨菪碱对X射线致放射性肺损伤的保护作用及机制。方法 将20只C57BL/6小鼠按随机数表法分为对照组、模型组（照射）、给药组（消旋山莨菪碱）、治疗组（照射+消旋山莨菪碱）,每组5只。给药组、治疗组照射前3天给予消旋山莨菪碱注射液腹腔注射（5 mg/kg）,模型组、治疗组给予6 MV X射线,18 Gy单次全胸腔照射,构建放射性肺损伤小鼠模型,辐照后治疗组采取每隔1天给药,连续给药6周后处死小鼠并取材。HE染色检测肺组织病理形态;酶联免疫吸附法（ELISA）检测肺泡灌洗液和血清中肿瘤坏死因子α（TNF-α）、白介素6（IL-6）、白介素1β（IL-1β）细胞因子表达;细胞衰老β-半乳糖苷酶（SA-β-Gal）染色检测肺组织细胞衰老情况;Western blot检测核因子E2相关因子2（Nrf2）、磷酸化NRF2（p-Nrf2）、p62蛋白表达。结果 与模型组相比,治疗组肺组织HE病理评分减低（t=8.66,P<0.01）;肺泡灌洗液中炎性细胞数量减少（t=10.70,P<0.01）、蛋白浓度降低（t=6.75,P<0.01）,血清TNF-α、IL-1β、IL-6表达减少（t=8.17、4.58、6.54,P<0.01）;肺组织SA-β-gal活性降低,且肺组织Nrf2、磷酸化Nrf2表达增强（t=6.42、7.30,P<0.01）,而p62表达减少（t=4.62,P<0.01）。结论 消旋山莨菪碱可通过减轻炎症等途径发挥对X射线致放射性肺损伤的保护作用,其保护机制可能与激活Nrf2通路,逆转辐照所致的细胞衰老有关。     

放射性肺损伤机制与防治新进展

胸部肿瘤患者在接受放射治疗过程中,常发生放射性肺损伤（放射性间质性肺炎和肺纤维化）,严重影响其生活质量。因此,放射性肺损伤的发病机制及防治研究对于肿瘤的放射治疗具有重要意义。本文就其研究进展进行综述,以期为进一步研究提供理论基础。