论文作者 韩勇
论文导师 刘锟,论文学位 博士,论文专业 外科学
论文单位 第四军医大学,点击次数 2,论文页数 90页File Size3381k
2002-03-01论文网 http://www.lw23.com/lunwen_605452567/ 肺癌,慢性阻塞性肺疾病,肿瘤易感性,α1抗胰蛋白酶,病例对照研究
lung cancer,chronic obstructive pulmonary disease,susceptibility to cancer,α1-antitrypsin, case-control study.
肺癌在我国恶性肿瘤造成的死亡中占首位，目前对其发病原因及其机理的研究尚无肯定的结论，因此在预防及治疗上尚无理想有效的方法。过去50年里吸烟被认为是发生肺癌的主要危险因素，大量的研究证实烟草中的芳香烃类致癌物对肺癌的发生起重要的作用，对其他危险因素的研究较少。尽管肺癌患者中有近80％的有吸烟史，然而最新的研究结果显示长期吸烟的人群中只有7-10％将发生肺癌，多数吸烟者并不发生肺癌。证实吸烟不是引起肺癌发病的唯一因素，个体对肺癌致癌物具有易感性。肺癌的家族聚集性也提示遗传基因在其发病中起着十分重要的作用。目前，人们已经发现在肺癌中有许多基因的改变，包括抑癌基因及癌基因等，而且在10几个染色体臂上发现有突变。但是，在这些基因中，很难找出对其易感性起作用的基因，因此可遗传的肿瘤易感性值得进一步深入研究。 第四军医大学博士论文5 被动吸烟、对致癌物的职业性暴露、空气污染、饮食因素以及油烟 的吸入都可能导致肺癌的发生，但都属于外界致癌物质的作用，对于机 体肺癌的易感性的研究一直没有明显进展。 在80年代有报道认为，非肿瘤性肺疾患包括矽肺、肺结核以及幼时 肺炎等可以增加肺癌的危险性，肺癌与哮喘等变态反应性疾病也有关系。 同时，我们在临床工作中发现，在肺癌患者中许多表现为肺功能减弱， 或胸部X线显示肺气肿改变明显，呼吸困难等，提示肺癌的发生可能与 肺部的功能状态有关。九十年代，美国uayo门imc杨平教授首先提出 肺气肿可能是肺癌发生的危险因素之一，为验证这个观点，及我国人群 的特征，我们首先进行了西安地区肺癌发病的危险因素的病例对照流行 病学研究，通过单因素及分层分析，发现吸烟、油烟污染暴露、精神创 伤史、家族肿瘤史、家族肺癌史、呼吸系统疾病史等是西安地区肺癌的 危险因素，而体育锻炼、新鲜蔬菜为肺癌的保护性因素。 为了进一步确定呼吸系统疾病史与肺癌的关系，我们对不同的呼吸 系统疾病与肺癌的危险性的关系进行了分析，结果发现具有慢性阻塞性 肺疾病（Chronic obstuctive Pulmonary Diseases，COPD）病史的患者， 肺癌发生的危险性明显增高。同时，肺功能的损伤增加了肺癌发生的危 险性。 COPD是肺部的一种慢性疾患，与肺癌有相同病因。早期研究认为， 吸烟可以导致COPD及肺癌。COPD与肺癌的危险性的关系与吸烟有关。 然而，我们的研究发现，在非吸烟人群中，有COPD病史发生肺癌的 几率高于没有COPD病史者。同时，在有COPD家族史的人群中，肺癌 的发生率明显升高。均提示COPD和肺癌易感性之间可能有着共同的基 因因素和／或病理学机制。 因此，研究COPD与肺癌的关系，及其相关易感基因，对于了解肺癌 的发病机理及其遗传易感性会提供很大帮助。进一步研究COPD和肺癌 第四军医大学博士论文（ 的共同致病因素，对这两种疾病的发生发展就有重要的意义。 蛋白酶、抗蛋白酶系统失衡引起的弹性蛋白酶和q－抗胰蛋白酶 （or；AT）之间平衡的失调是COPD产生的重要影响因素。其中a；AT缺 陷…；AD）是西方国家人群中导致肺气肿的重要原因。据此，a；AT成为我 们进一步研究的目标。通过免疫组织化学方法，我们对a；AT在肺癌组织的表达情况及病理学意义进行了研究，结果发现，OAT在肺癌组织中的 表达明显升高。a；f的表达与肺癌的临床分期相关，表明qAT可能与 肺癌的产主、发展、演进等生物学特征相关。我们同时发现，肺癌患者 血清a；AT的水平明显降低。a人活性降低使个体发展为肺癌的危险性 增加。我们有理由推测由于。，AT缺乏导致的弹性蛋白酶／抗弹性蛋白酶平 衡系统的夫衡，进而产生的肺组织损伤可能是肺癌发生的前期病变和刃 要基础。 a；AT基因有70多个亚型，其中PIZ、PIS等亚型会引起a．AD。我什］ 在正常对照组及肺癌患者中未发现N，PIS a人基因表型，说明在我 国人群中n，PIS分布极少，然而在a；AT活性降低者中山未发现n， PIS aAT基因亚型，而是接近n 型的 PCR片断。因此，大样本的a；AT 的研究可能会发现中国人群特有的a人缺乏的新基因亚型。 总之，我们的研究结果表明：具有COPD病史的患者，发生肺癌的危 险性明显增高。同时，肺功能的损伤增加了肺癌发生的危险性。aAT在 肺癌组织中的表达明显升高。a；AT表
Carcinoma of the lung has been the leading cause of cancer death in China for decades. No certain results have been given on the mechanism of its development. Tobacco use especially cigarette smoking has been recognized as a major risk factor for nearly 50 years. Extensive and worldwide epidemiological investigations have provided evidence for the causal role of tobacco in lung cancer, yet little attention has been given on other risk factors of lung cancer. However, despite the fact that tobacco smoke is the culprit for over 80% of current lung cancer occurrence, only 7-10% of all lung-term heavy smokers will develop this disease. It indicates that besides tobacco smoking, theremight be some other risk factors that play important roles in the development of lung cancer. Individual susceptibility to carcinogen exposures is indisputable, and the familial aggregation of lung cancer also suggested that inherited genes may be important in the development of lung cancer. In lung cancer a wide range of genetic alterations have been reported among tumor suppressor genes, oncogenes, and DMA mismatch repair genes, and loss of heterozygosity has been found from more than 10 different chromosomal arms. However it is difficult to distinguish the genes playing a role in cancer susceptibility, and the inherited susceptibility to lung cancer therefore needs a further investigation.Passive smoking, occupational exposure to carcinogen, air pollute, diet and cooking smoke are regarded as risk factors of lung cancer, but they all acted as carcinogen exposures. Up to date, no major steps were taken in the researching of susceptibility to lung cancer.A previous history of non-neoplastic disease including asbestosis, silicosis, tuberculosis and pneumonia had been reported to increase lung cancer risk in 1980", and a positive association of lung cancer with asthma, allergies has been reported inconsistently. In the meantime, in our clinical work, lung function damage has been found in many lung cancer patients who presented lower FEV1% and emphysema on X ray film, even dyspnea. Professor Ping Yang in Mayo Clinic reported the COPD might be a risk factor of lung cancer, the development of lung cancer might be related to the functional status of the lung.As an initial step to verify this hypothesis, the lung cancer risk factors among population in Xi"an was investigated in the present study.The analysis of lung cancer risk factors was based on the data of a case-control study conducted during 1999-2001 in Xi"an, China, and correlation power of all the risk factors and lung cancer was evaluated by the odd ratio (OR). The results indicated that tobacco smoking, air pollutes, cooking smoke, history of previous lung diseases, family history of tumor, family history of lung cancer and psychic trauma were the main risk factors of lung cancer, however, physical practice and fresh vegetables were the protective factors.To further investigate the relationship between history of previous lung diseases and lung cancer, patients with different lung diseases and the risk of lung cancer were analyzed. The results show that the patients with Chronic Obstructive Pulmonary Diseases (COPD) had an increased risk of lung cancer. Furthermore, the impairment of lung function was observed to increase the risk of lung cancer.COPD is the only group of chronic pulmonary non-malignant diseases that share a common etiology with lung cancer. Earlier studies suggested that lung cancer and COPD could both be due to cigarette smoking. The relationship between COPD and the risk of lung cancer was affected by smoking, therefore, COPD could not be distinguished as an independent risk factor for lung cancer. However, our study demonstrated that even in nonsmokers the risk of lung cancer in people with COPD is higher than those without COPD. Furthermore, people with a family history of COPD will be a candidate to have an increased risk of lung cancer. All of these evidence suggest a possibility of having a common genetic factors and /or pathological