炎症诱导酶在大鼠肺鳞癌发生发展中的表达

Expression of inflammation related enzymes during experimental rat lung carcinogenesis

目的 研究参与炎症的重要诱导酶———环氧化酶 2 (COX 2 )和诱导型一氧化氮合酶(iNOS)在大鼠肺鳞癌癌变及进展各阶段的表达情况 ,探讨非甾体类抗炎药 (COX 2表达抑制剂 )和iNOS抑制剂防治肺鳞癌的可能性。方法 Wistar大鼠 80只 ,左肺下叶支气管灌注致癌质碘油 ,分批处死获取肺鳞癌发生发展各阶段标本。免疫组化检测各阶段病变组织COX 2、iNOS的表达并计算免疫组化评分 (IHS) ,各阶段IHS与前一阶段比较。结果 获取支气管黏膜上皮增生 14例 ,鳞状化生 2 5例 ,不典型增生 33例 ,原位癌 12例 ,侵袭癌 5 4例 ,转移癌 17例。支气管黏膜增生、鳞状化生、不典型增生等癌前病变有炎症发生及COX 2、iNOS表达上调。不典型增生、原位癌及转移癌阶段COX 2的IHS增高有显著性 (P <0 .0 1,P <0 .0 5 ,P <0 .0 1) ,支气管黏膜上皮增生及转移癌阶段iNOS的IHS增高有显著性 (P <0 .0 5 ,P <0 .0 1)。COX 2与iNOS表达呈正相关 (r =0 .6 0 16 ,P <0 .0 0 1)。结论COX 2、iNOS在肺鳞癌发生及发展中有一定作用 ,可能是联系炎症与肿瘤发生的分子机制之一 ,非甾体类抗炎药物和iNOS抑制剂化学预防支气管不典型增生、肺鳞癌的发生及肺鳞癌的转移 ,将会取得较好的效果。

Objective To investigate the expression of two inflammation related enzymes cyclooxygenase 2 (COX 2) and inducible nitric oxide synthase (iNOS) during the experimental rat lung carcinogenesis. Methods Eighty Wistar rats were instilled with 3 methylcholanthrene (MCA) and diethylinitrosamine (DEN) into the left lobar branchus to induce lung squamous cell carcinoma. To obtain specimen in every pathological phase during the carcinogenesis, these rats were sacrificed at different intervals. The expression of COX 2 and iNOS in every pathological phase during the carcinogenesis were examined by immunohistochemical method. The immunohistochemical scores (IHS) were calculated by combining an estimate of the percentage of immunoreactive cells with that of the stain intensity. Results 155 specimens of every pathological phase during the carcinogenesis showed: hyperplasia 14, squamous metaplasia 25, dysplasia 33, carcinoma in situ 12, infiltrating carcinoma 54 and metastasis 17. Inflammation and elevated expressions of COX 2 and iNOS were shown in the precancerous lesions. The COX 2 IHS was significantly increased in dysplasia, carcinoma in situ and metastasis( P <0.01, P < 0.05, P <0.01 respectively). The iNOS IHS significantly increased in hyperplasia and metastasis( P < 0.05, P <0.01 respectively). There was a positive correlation between the expression of COX 2 and iNOS (γ=0.601 6, P <0.001). Conclusion COX 2 and iNOS, two inflammation related enzymes, playing important roles in the carcinogenesis of MCA and DEN, induce rat lung squamous cell carcinoma as well as its metastasis. The relation between inflammation and carcinogenesis may partly be explained by the elevated expression of these two enzymes. Nonsteroidal antiinflammatory drug (COX 2 inhibitors) and iNOS inhibitors may possess antitumor activities because of their prevention of bronchial dysplasia, carcinogenesis and metastasis.