Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice
Pulmonary prostacyclin synthase overexpression chemoprevents tobacco smoke lung carcinogenesis in mice
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DOI：
10.1158/0008-5472.can-04-1070
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发表时间：
2004-08-15
期刊：
影响因子：
11.2
通讯作者：
Geraci, MW
中科院分区：
文献类型：
--
作者：
Keith, RL;Miller, YE;Geraci, MW
在化学诱导的小鼠肺癌模型中，通过肺特异性前列环素合酶过度表达增加肺前列腺素12（前列环素）的产生降低了肺肿瘤的发生率和多样性。我们假设肺前列环素合酶过表达可以预防烟草烟雾暴露小鼠的肺癌发生。小鼠暴露于烟草烟雾是诱导肺腺癌的既定模型，并允许测试潜在的化学预防策略。将肺特异性前列环素合酶过表达的转基因FVB/N小鼠暴露于主流香烟烟雾22周，然后再保持20周不暴露。所有接触的动物都出现了细支气管炎，类似于吸烟者的呼吸性细支气管炎。与吸烟转基因阴性同窝小鼠相比，转基因小鼠的肿瘤发生率和多样性显著降低。与野生型同窝仔的肿瘤发生率（19只中的16只; 84%; Fisher精确检验，P = 0.012）相比，转基因动物（15只中的6只; 40%）发生肿瘤的数量显著减少。转基因动物的肿瘤多样性也显著降低（tg（+）= 0.4 +/-0.5 vs野生型= 1.2 +/-0.86肿瘤/小鼠; P < 0.001）。处死时的目标前列腺素水平显示转基因动物中前列腺素12水平显著升高，同时前列腺素E-2水平显著降低。分离的II型肺细胞的基因表达分析表明所观察到的化学预防的潜在解释，与Western印迹分析证实细胞色素p450 2 e1的表达降低。这些研究扩展了我们以前的研究，并证明在烟草烟雾暴露模型中，操纵环氧合酶远端的前列腺素产生显著降低了肺癌的发生，基因表达研究显示了抗氧化、免疫反应和细胞因子途径的关键改变。
Increased pulmonary production of prostaglandin 12 (prostacyclin) by lung-specific overexpression of prostacyclin synthase decreases lung tumor incidence and multiplicity in chemically induced murine lung cancer models. We hypothesized that pulmonary prostacyclin synthase overexpression would prevent lung carcinogenesis in tobacco-smoke exposed mice. Murine exposure to tobacco smoke is an established model of inducing pulmonary adenocarcinomas and allows for the testing of potential chemopreventive strategies. Transgenic FVB/N mice with lung-specific prostacyclin synthase overexpression were exposed to mainstream cigarette smoke for 22 weeks and then held unexposed for an additional 20 weeks. All of the exposed animals developed bronchiolitis analogous to the respiratory bronchiolitis seen in human smokers. The transgenic mice, when compared with smoke-exposed transgene negative littermates, had significant decreases in tumor incidence and multiplicity. Significantly fewer transgenics (6 of 15; 40%) developed tumors compared with the tumor incidence in wild-type littermates (16 of 19; 84%; Fisher's exact test, P = 0.012). Tumor multiplicity was also significantly decreased in the transgenic animals (tg(+) = 0.4 +/- 0.5 versus wild-type = 1.2 +/- 0.86 tumors/mouse; P < 0.001). Targeted prostaglandin levels at the time of sacrifice revealed significantly elevated prostaglandin 12 levels in the transgenic animals, coupled with significantly decreased prostaglandin E-2 levels. Gene expression analysis of isolated type II pneumocytes suggests potential explanations for the observed chemoprevention, with Western blot analysis confirming decreased expression of cytochrome p450 2e1. These studies extend our previous studies and demonstrate that manipulation of prostaglandin production distal to cyclooxygenase significantly reduces lung carcinogenesis in a tobacco smoke exposure model, and gene expression studies show critical alterations in antioxidation, immune response, and cytokine pathways.