Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.
Levels of prostaglandin E metabolite and leukotriene E(4) are increased in the urine of smokers: evidence that celecoxib shunts arachidonic acid into the 5-lipoxygenase pathway.
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DOI：
10.1158/1940-6207.capr-09-0005
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发表时间：
2009-04
期刊：
影响因子：
--
通讯作者：
Dannenberg AJ
中科院分区：
文献类型：
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作者：
Duffield-Lillico AJ;Boyle JO;Zhou XK;Ghosh A;Butala GS;Subbaramaiah K;Newman RA;Morrow JD;Milne GL;Dannenberg AJ
环氧合酶-2（考克斯-2）和5-脂氧合酶（5-LO）在炎症和肿瘤发生中起作用。需要反映烟草烟雾诱导的组织损伤的生物标志物。在这项研究中，尿前列腺素E代谢物（PGE-M）和白三烯E4（LTE 4），考克斯和5-LO途径的生物标志物，在从不吸烟者，以前吸烟者和目前吸烟者的水平进行了比较。测定了选择性考克斯-2抑制剂塞来昔布对PGE-M和LTE 4水平的影响。PGE-M和LTE 4的基线水平与吸烟状态呈正相关;目前吸烟者的PGE-M和LTE 4水平高于从不吸烟者。塞来昔布200 mg bid治疗6 ± 1天，导致所有组的尿PGE-M水平降低，但在基线PGE-M水平高的受试者中效果最大。因此，吸烟者的高基线PGE-M水平反映了考克斯-2活性的增加。在基线PGE-M水平高的个体中，塞来昔布治疗导致尿LTE 4水平显著增加，在基线PGE-M水平低的个体中未发现这种效应。总之，在吸烟者中发现尿PGE-M和LTE 4水平升高，这一结果可能反映了亚临床肺部炎症。在PGE-M基线水平高（考克斯-2活性升高）的个体中，塞来昔布给药将花生四烯酸分流到促炎性5-LO通路中。由于5-LO活性和LTE 4被认为在心血管疾病中发挥作用，这些结果可能有助于解释使用考克斯-2抑制剂和心血管并发症之间的联系。
Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) play a role in inflammation and carcinogenesis. Biomarkers that reflect tobacco smoke-induced tissue injury are needed. In this study, levels of urinary prostaglandin E metabolite (PGE-M) and leukotriene E4 (LTE4), biomarkers of the COX and 5-LO pathways, were compared in never smokers, former smokers and current smokers. The effects of celecoxib, a selective COX-2 inhibitor, on levels of PGE-M and LTE4 were determined. Baseline levels of PGE-M and LTE4 were positively associated with smoking status; levels of PGE-M and LTE4 were higher in current vs. never smokers. Treatment with celecoxib 200 mg bid for 6 ± 1 days led to a reduction in urinary PGE-M levels in all groups, but exhibited the greatest effect among subjects with high baseline PGE-M levels. Thus, high baseline PGE-M levels in smokers reflected increased COX-2 activity. In individuals with high baseline PGE-M levels, treatment with celecoxib led to a significant increase in levels of urinary LTE4, an effect that was not found in individuals with low baseline PGE-M levels. In conclusion, increased levels of urinary PGE-M and LTE4 were found in human smokers, a result that may reflect subclinical lung inflammation. In individuals with high baseline levels of PGE-M (elevated COX-2 activity), celecoxib administration shunted arachidonic acid into the pro-inflammatory 5-LO pathway. Because 5-LO activity and LTE4 have been suggested to play a role in cardiovascular disease, these results may help to explain the link between use of COX-2 inhibitors and cardiovascular complications.