Mao Jenny T, Tsu I-Hsien, Dubinett Steven M, Adams Bradley, Sarafian Theodore, Baratelli Felicita, Roth Michael D, Serio Kenneth J
Division of Pulmonary and Critical Care Medicine, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, California 90095-1690, USA.
Clin Cancer Res. 2004 Oct 15;10(20):6872-8. doi: 10.1158/1078-0432.CCR-04-0945.
Emerging data continue to link carcinogenesis to inflammatory events involving the eicosanoid metabolic pathways. We therefore evaluated the effects of cyclooxygenase (COX)-2 inhibition on leukotriene (LT) B(4) synthesis in the lungs of active smokers, as part of a pilot lung cancer chemoprevention study with celecoxib (Celebrex), an oral COX-2 inhibitor.
Bronchoalveolar lavage was performed before celecoxib treatment and after 1 month of celecoxib treatment to recover alveolar macrophages (AMs) and lining fluid for study. After harvest, AMs were immediately stimulated in vitro with the calcium ionophore A23187. AMs obtained from smokers before treatment and from ex-smoker control subjects were also cultured overnight with SC58236, a selective COX-2 inhibitor, with or without lipopolysaccharide stimulation.
Treatment with oral celecoxib only modestly increased LTB(4) levels in bronchoalveolar lavage, without increasing the mRNA transcription of 5-lipoxygenase (5-LOX) or 5-LOX-activating protein in AMs, whereas the acute calcium ionophore-stimulated LTB(4) production from smokers' AMs was markedly increased by 10.6-fold. In addition, smokers' AMs were twice as responsive in producing LTB(4) when exposed to lipopolysaccharide compared with ex-smokers' AMs. Concomitant COX-2 inhibition with SC58236, however, did not significantly impact these changes, whereas the 5-LOX inhibitor Zileuton blocked the generation of LTB(4) in a dose-responsive manner. Finally, cycloheximide increased the production of LTB(4) under all conditions, suggesting a shunting phenomenon and/or the presence of pathway inhibitors.
Our findings suggest that whereas oral celecoxib is capable of modulating LTB(4) production in the lung microenvironment, under physiologic conditions, this effect is probably not functionally significant.
新出现的数据继续将致癌作用与涉及类花生酸代谢途径的炎症事件联系起来。因此，作为一项使用口服环氧化酶（COX）-2抑制剂塞来昔布（西乐葆）进行的肺癌化学预防试点研究的一部分，我们评估了COX-2抑制对现吸烟者肺部白三烯（LT）B4合成的影响。
在塞来昔布治疗前和治疗1个月后进行支气管肺泡灌洗，以获取肺泡巨噬细胞（AM）和衬里液用于研究。收获后，立即用钙离子载体A23187在体外刺激AM。来自治疗前吸烟者和戒烟者对照受试者的AM也用选择性COX-2抑制剂SC58236培养过夜，有无脂多糖刺激。
口服塞来昔布治疗仅适度增加支气管肺泡灌洗中LTB4水平，而不增加AM中5-脂氧合酶（5-LOX）或5-LOX激活蛋白的mRNA转录，而急性钙离子载体刺激吸烟者AM产生的LTB4明显增加了10.6倍。此外，与戒烟者的AM相比，吸烟者的AM在暴露于脂多糖时产生LTB4的反应性是其两倍。然而，用SC58236同时抑制COX-2并没有显著影响这些变化，而5-LOX抑制剂齐留通以剂量反应方式阻断LTB4的生成。最后，放线菌酮在所有条件下均增加LTB4的产生，提示存在分流现象和/或途径抑制剂。
我们的研究结果表明，虽然口服塞来昔布能够调节肺微环境中LTB4的产生，但在生理条件下，这种作用可能在功能上并不显著。
