Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice
Celecoxib reduces pulmonary inflammation but not lung tumorigenesis in mice
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DOI：
10.1093/carcin/23.10.1653
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发表时间：
2002-10-01
期刊：
影响因子：
4.7
通讯作者：
Malkinson, AM
中科院分区：
文献类型：
--
作者：
Kisley, LR;Barrett, BS;Malkinson, AM
环氧合酶（考克斯）酶表达在人类和啮齿类动物肺肿瘤中升高，并且非甾体抗炎药（NSAID）如吲哚美辛减少小鼠肺肿瘤形成。这些观察结果，沿着NSAID治疗对结肠癌产生的良好保护作用，促使临床试验测试塞来昔布，一种考克斯-2特异性抑制剂，是否可以预防高危人群中肺癌的发展。塞来昔布在肺部炎症和肺肿瘤发生的小鼠模型中的保护作用尚未得到评价，然而，我们现在报告此类研究。对小鼠长期给予丁基羟基甲苯（BHT）可刺激肺部炎症，其特征为血管渗漏和巨噬细胞浸润到空气间隙中，PGE（2）产生增加，以及5-脂氧合酶（5-LO）从细胞质转移到颗粒部分。饮食塞来昔布限制巨噬细胞浸润，废除PGE（2）的生产和减少颗粒5-LO含量。塞来昔布和阿司匹林在预防肺癌发生的两阶段致癌方案中无效，其中3-甲基胆蒽给药后是慢性BHT。塞来昔布也没有减少乌拉坦诱导后肺肿瘤的多样性;塞来昔布治疗小鼠的肺肿瘤大于未接受塞来昔布的小鼠。在塞来昔布喂养的小鼠中诱发的肿瘤含有的PGE（2）比在对照饮食喂养的小鼠中的肿瘤少60%，因此降低肺PGE（2）水平不足以防止肺肿瘤形成。由于除了PGE（2）外，类花生酸的产生也受到塞来昔布的抑制，并且由于塞来昔布具有COX非依赖性相互作用，因此其对肿瘤形成的影响在不同器官系统中可能不同。
Cyclooxygenase (COX) enzyme expression is elevated in human and rodent lung tumors, and non-steroidal anti-inflammatory drugs (NSAIDs) such as indomethacin reduce lung tumor formation in mice. These observations, along with the well-characterized protection that NSAID treatment engenders for colon cancer, have prompted clinical trials testing whether celecoxib, a COX-2-specific inhibitor, can prevent lung cancer development in populations at high risk. Protection by celecoxib in murine models of pulmonary inflammation and lung tumorigenesis has not yet been evaluated, however, and we now report such studies. Chronic administration of butylated hydroxytoluene (BHT) to mice stimulates pulmonary inflammation characterized by vascular leakage and macrophage infiltration into the air spaces, increased PGE(2) production, and translocation of 5-lipoxygenase (5-LO) from the cytosol to the particulate fraction. Dietary celecoxib limited macrophage infiltration, abrogated PGE(2) production and reduced particulate 5-LO content. Celecoxib and aspirin were ineffective at preventing lung tumorigenesis in a two-stage carcinogenesis protocol in which 3-methylcholanthrene administration is followed by chronic BHT. Celecoxib also did not reduce the multiplicity of lung tumors after induction by urethane; lung tumors in celecoxib-treated mice were larger than those in mice that did not receive celecoxib. Tumors induced in celecoxib-fed mice contained 60% less PGE(2) than tumors in mice fed control diets, so reducing lung PGE(2) levels was insufficient to prevent lung tumor formation. As the production of eicosanoids in addition to PGE(2) is also inhibited by celecoxib, and as celecoxib has COX-independent interactions, its effects on tumor formation may vary in different organ systems.