【作者】 杨杰；

【导师】 李君文；

【作者基本信息】 中国人民解放军军事医学科学院 ， 劳动卫生与环境卫生学， 2006， 博士

【摘要】 研究目的：在世界范围内，肺癌是所有恶性肿瘤中发病率和死亡率最高的肿瘤。吸烟是肺癌公认的最主要的致病因素。本文将利用被动吸烟致小鼠肺癌模型，从氧化及抗氧化、免疫、凋亡和基因水平探讨肺癌发病的原因及防治机理，为化学预防被动吸烟所导致的肺癌提供依据。 研究方法：1．建立被动吸烟致小鼠肺癌模型、抗氧化剂干预模型、苯并(a)芘(BP)复合雌二醇(E2)致雌性小鼠肺癌模型和烟草提取液(CSE)转化胚肺细胞(ELC)模型；2．检测小鼠血清及线粒体中SOD、MDA、GSH-PX、ROS与VE水平；小鼠肺组织细胞及胚肺细胞的DNA含量、凋亡及细胞周期，脾淋巴细胞转化率，血液及肺组织的端粒长度及小鼠全基因组的表达谱变化。 结果与结论： 1．应用昆明系小鼠成功地建立了被动吸烟导致肺癌及抗氧化剂干预模型，为下一步肺癌机理的研究奠定了基础。肺癌的发生有性别差异，三个VE干预组雌性小鼠的发病率和发病数都明显高于雄性小鼠。在降低被动吸烟导致小鼠肺癌方面，高剂量VE效果最好，中低剂量次之，槲皮素效果最差。 2．BP复合E2组肺癌发病率和发病数都明显高于BP单纯作用组、雄性作用组和三个对照组(p＜0.05)，表明雌激素对雌性小鼠肺癌的发生具有促进作用。VE干预各组小鼠的肺癌发病率和发病数明显高于对照各组及BP单独作用组(p＜0.05)，显示VE具有促进或加强BP致雌性小鼠肺癌发生的作用。 3．CSE对ELC增值能力有明显抑制作用，可诱导ELC发生凋亡及细胞周期发生改变，并存在剂量-效应关系；VE对CSE导致ELC损伤有保护作用，使凋亡比例下降，并使细胞周期的比例接近正常。 4．SOD活力降低及ROS活力升高的水平与各组肺癌发病率和发病数相一致，被动吸烟导致小鼠肺癌的发病率和发病数与其对小鼠免疫系统损伤规律相一致。VE能防止被动吸烟导致的细胞凋亡、细胞周期改变和DNA损伤，而槲皮素在清除ROS和抵抗氧化损伤、细胞凋亡、细胞周期改变的效果不理想。 5．在BP复合E2致小鼠肺癌实验中肺癌高发的各组，ROS也增高，说明BP复合E2导致小鼠肺癌可能也是通过氧化应激途径而产生，但VE干预无效，提示可能更多还原

【Abstract】 Object: Worldwide, the lung cancer is not only the most common tumor, but also the tumor of supreme incidence and death rate in all malignant tumor. Smoking is the main cause of lung cancer. So, explore the reason of lung cancer and ask the clear protective measure effective to passive smoker to seem very important and urgent. In this study, we will use mouse lung cancer model induced by passive smoking to explore the reason of lung cancer and mechanism of intervention in oxidant and anti-oxidant, immune response, apoptosis and gene level. In the end, we will give useful method and theoretical foundation to prevent the lung cancer induced by passive smoking.Method: 1 Development of mouse lung cancer model induced by passive smoking,BP combines 17β-estradiol model, antioxidant intervention model and Embryo lung cells translation model induced by cigarette smoke extract(CSE).2 To measure SOD, MDA , GSH-PX , ROS and VE level of serum and mitochondria;ELC DNA content, apoptosis and cell cycle of mouse lung cell and ELC; the spleen Lymphocyte transformation index; the length of telomere of blood and lung DNA; the mice lung gene change using Affymetrix MOE 430 2.0 gene expression chip.Results and Conclusion:1.It is succeeds in using Kunming strain mice to produce lung tumor model and antioxidant to intervene model by inhalation of tobacco smoke that have established the good foundation for the research of next lung cancer mechanism. There are gender differences in the incidence and multiplicity of lung cancer,that of female mice in three vitamin E(VE) intervene group are all higher than that of male mice. 2.The incidence of BP combines E2 group is obvious higher than BP simple function group,male intervention group and three control group,that prove the estrogen has facilitation to the development of female mouse lung cancer. Lung cancer incidence of every VE intervene group is higher than every control group and BP group alone obviously. The high incidence of lung cancer of VE intervene group proves VE facilitate to female mouse lung cancer indirectly,更多还原