烟草致癌原NNK诱发大鼠肺癌前病变的实验研究  

Induction of pulmonary precancerous lesions by tobacco-specific NNK in Wistar rats

作　　者：张玉霞[1] 赖百塘[2] 陈洪雷[1] 岳文涛[2] 杨飞[1] 夏东[1] 肖静[1] 叶波[1] 刘铭球[1] 

机构地区：[1]武汉大学医学院病理学系,430071 [2]北京市结核病胸部肿瘤研究所

出　　处：《中国肺癌杂志》2006年第2期152-156,共5页Chinese Journal of Lung Cancer

摘　　要：背景与目的4(甲基亚硝胺基)1(3吡啶)1丁酮[4(methylnitrosamino)1(3pyridyl)1butanone,NNK]是烟草中主要的致癌原。为了研究NNK的致癌机制,寻找针对NNK所致肺癌的有效的化学防护措施,建立以NNK诱发的动物模型是非常有效的研究手段。本研究的目的是观察一次性支气管灌注NNK致Wistar大鼠的肺组织的病理变化,并探讨病变发生机制。方法实验组Wistar大鼠15只,左肺叶下部支气管内灌注含NNK50mg/kg(高剂量组,5只)或25mg/kg(低剂量组,10只)的碘油溶液0.1mL,X线影像学监测病变进展。另15只Wistar大鼠灌注不含NNK的碘油,作为对照。HE染色观察大鼠肺组织病理变化,免疫组化SP法检测AE1/AE3、PCNA、p53蛋白表达。结果灌注碘油后数字减影血管造影(digitalsubtractionangiography,DSA)显示碘油分布于大鼠左肺叶下部,第107天DSA显示左肺叶下部的碘油影像消失。实验组67%(10/15)的大鼠(高剂量组4只,低剂量组6只)左肺下部见绿豆大小的结节状实变病灶。HE染色示实验组100%(15/15)的大鼠左肺组织出现局灶性肺泡细胞的不典型增生,肺泡间隔增宽,肺泡腔狭窄;67%(10/15)的大鼠左肺有腺上皮的高度不典型增生,部分增生的细胞构成小腺体,偶见异型增生腺体向支气管壁的肌层侵犯。免疫组化染色显示实验组不典型增生细胞的角蛋白AE1/AE3阳性。PCNA在对照组和NNK低、高剂量组的阳性表达率分别为13%(2/15)、90%(9/10)、100%(5/5),后两者与对照组的差异均有统计学意义(P=0.000,P=0.001),而低、高剂量组之间差异无统计学意义(P=1.000)。p53蛋白在对照组肺组织中表达为阴性,在NNK低、高剂量组中表达率分别为50%(5/10)和60%(3/5),均较对照组明显升高(P=0.005,P=0.009),而低、高剂量组之间差异无统计学意义(P=1.000)。结论对Wistar大鼠的左肺叶支气管灌注含NNK的碘油溶液可在局部诱发肺泡细胞和腺上皮的不典型增生。该模型可用于烟草致肺癌�Background and objective Tobacco-specific 4-（methylnitrosamino）-1-（3-pyriclyl）-1-butanone （NNK） is the most important carcinogen in cigarette. Models induced by NNK are widely used in investigations about the mechanisms of pulmonary neoplasia ancl chemoprevention studies. The aim of this study is to explore the pulmonary precancerous lesions induced by NNK ancl its possible mechanisms. Methods Fifteen Wistar rats were divided into two trial groups, in which the high-dose group was instilled with iodized oil including 10 mg （50 mg/kg） NNK into the left lower lobar bronchus, and the low-dose group received 5 mg （25 mg/kg） NNK. Another 15 Wistar rats were instilled only with iodized oil as control group. All rats were examined immediately after instillation and followed up periodically by pulmogram. The pulmonary tissues of rats were pathologically examined, and the expression of AE1/AE3, PCNA and p53 was detected by immunohistochemieal method. Results The pulmograms showed that the iodized oil localized at the bottom of left lobe and disappeared 107 days later. In trial group, 10 of 15 rats （67%） had nodus at the bottom of left lobe. All of rats in trial group （15/15） displayed atypical hyperplasia in alveolar region, showing single or multiple layers of proliferative epithelial cells along intact alveolar septa with irregular and non-discrete margins of lesion, but continuous alveolar spaces were not obliterated by proliferative epithelial cells. Ten of 15 rats in trial group showed severe atypical hyperplasia of glandular epithelium with occasional infiltrating to mucular layer.All of those atypical hyperplasia sells showed positive AE1/AE3 expression.The positive rate of PCNA was 90% （9/10） and 100%（5/5） in low-dose group and high-dose group respectively,which was significantly higher than that in control group（13%,2/15）（P=0.000,P=0.001）.The positive rate of p53 expression was 50%（5/10） and 60%（3/5） in low-dose group and high-dose group respectively,which was s

关 键 词：NNK 肺肿瘤 WISTAR大鼠 P53蛋白 

分 类 号：R734.2[医药卫生—肿瘤]