論文作者 韓勇
論文導師 劉錕,論文學位 博士,論文專業 外科學
論文單位 第四軍醫大學,點擊次數 2,論文頁數 90頁File Size3381k
2002-03-01論文網 http://www.lw23.com/lunwen_605452567/ 肺癌,慢性阻塞性肺疾病,腫瘤易感性,α1抗胰蛋白酶,病例對照研究
lung cancer,chronic obstructive pulmonary disease,susceptibility to cancer,α1-antitrypsin, case-control study.
肺癌在我國惡性腫瘤造成的死亡中占首位，目前對其發病原因及其機理的研究尚無肯定的結論，因此在預防及治療上尚無理想有效的方法。過去50年里吸煙被認為是發生肺癌的主要危險因素，大量的研究證實煙草中的芳香烴類致癌物對肺癌的發生起重要的作用，對其他危險因素的研究較少。盡管肺癌患者中有近80％的有吸煙史，然而最新的研究結果顯示長期吸煙的人群中只有7-10％將發生肺癌，多數吸煙者并不發生肺癌。證實吸煙不是引起肺癌發病的唯一因素，個體對肺癌致癌物具有易感性。肺癌的家族聚集性也提示遺傳基因在其發病中起著十分重要的作用。目前，人們已經發現在肺癌中有許多基因的改變，包括抑癌基因及癌基因等，而且在10幾個染色體臂上發現有突變。但是，在這些基因中，很難找出對其易感性起作用的基因，因此可遺傳的腫瘤易感性值得進一步深入研究。 第四軍醫大學博士論文5 被動吸煙、對致癌物的職業性暴露、空氣污染、飲食因素以及油煙 的吸入都可能導致肺癌的發生，但都屬于外界致癌物質的作用，對于機 體肺癌的易感性的研究一直沒有明顯進展。 在80年代有報道認為，非腫瘤性肺疾患包括矽肺、肺結核以及幼時 肺炎等可以增加肺癌的危險性，肺癌與哮喘等變態反應性疾病也有關系。 同時，我們在臨床工作中發現，在肺癌患者中許多表現為肺功能減弱， 或胸部X線顯示肺氣腫改變明顯，呼吸困難等，提示肺癌的發生可能與 肺部的功能狀態有關。九十年代，美國uayo門imc楊平教授首先提出 肺氣腫可能是肺癌發生的危險因素之一，為驗證這個觀點，及我國人群 的特征，我們首先進行了西安地區肺癌發病的危險因素的病例對照流行 病學研究，通過單因素及分層分析，發現吸煙、油煙污染暴露、精神創 傷史、家族腫瘤史、家族肺癌史、呼吸系統疾病史等是西安地區肺癌的 危險因素，而體育鍛煉、新鮮蔬菜為肺癌的保護性因素。 為了進一步確定呼吸系統疾病史與肺癌的關系，我們對不同的呼吸 系統疾病與肺癌的危險性的關系進行了分析，結果發現具有慢性阻塞性 肺疾病（Chronic obstuctive Pulmonary Diseases，COPD）病史的患者， 肺癌發生的危險性明顯增高。同時，肺功能的損傷增加了肺癌發生的危 險性。 COPD是肺部的一種慢性疾患，與肺癌有相同病因。早期研究認為， 吸煙可以導致COPD及肺癌。COPD與肺癌的危險性的關系與吸煙有關。 然而，我們的研究發現，在非吸煙人群中，有COPD病史發生肺癌的 幾率高于沒有COPD病史者。同時，在有COPD家族史的人群中，肺癌 的發生率明顯升高。均提示COPD和肺癌易感性之間可能有著共同的基 因因素和／或病理學機制。 因此，研究COPD與肺癌的關系，及其相關易感基因，對于了解肺癌 的發病機理及其遺傳易感性會提供很大幫助。進一步研究COPD和肺癌 第四軍醫大學博士論文（ 的共同致病因素，對這兩種疾病的發生發展就有重要的意義。 蛋白酶、抗蛋白酶系統失衡引起的彈性蛋白酶和q－抗胰蛋白酶 （or；AT）之間平衡的失調是COPD產生的重要影響因素。其中a；AT缺 陷…；AD）是西方國家人群中導致肺氣腫的重要原因。據此，a；AT成為我 們進一步研究的目標。通過免疫組織化學方法，我們對a；AT在肺癌組織的表達情況及病理學意義進行了研究，結果發現，OAT在肺癌組織中的 表達明顯升高。a；f的表達與肺癌的臨床分期相關，表明qAT可能與 肺癌的產主、發展、演進等生物學特征相關。我們同時發現，肺癌患者 血清a；AT的水平明顯降低。a人活性降低使個體發展為肺癌的危險性 增加。我們有理由推測由于。，AT缺乏導致的彈性蛋白酶／抗彈性蛋白酶平 衡系統的夫衡，進而產生的肺組織損傷可能是肺癌發生的前期病變和刃 要基礎。 a；AT基因有70多個亞型，其中PIZ、PIS等亞型會引起a．AD。我什］ 在正常對照組及肺癌患者中未發現N，PIS a人基因表型，說明在我 國人群中n，PIS分布極少，然而在a；AT活性降低者中山未發現n， PIS aAT基因亞型，而是接近n 型的 PCR片斷。因此，大樣本的a；AT 的研究可能會發現中國人群特有的a人缺乏的新基因亞型。 總之，我們的研究結果表明：具有COPD病史的患者，發生肺癌的危 險性明顯增高。同時，肺功能的損傷增加了肺癌發生的危險性。aAT在 肺癌組織中的表達明顯升高。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