Schildknecht Stefan, Bachschmid Markus, Baumann Achim, Ullrich Volker
Department of Biology, University of Konstanz, Konstanz, Germany.
FASEB J. 2004 Apr;18(6):757-9. doi: 10.1096/fj.03-0609fje. Epub 2004 Feb 20.
High levels of prostacyclin (PGI2; measured as 6-keto-PGF1alpha) have been reported in patients under septic shock. Because this was at variance with our previous findings of nitration and inhibition of PGI2 synthase by endotoxin (LPS) in the endothelium, we examined the role of vascular smooth muscle as an alternative source of PGI2. Bovine aortic smooth muscle cells (SMC) in passage 1 contained high levels of PGI2 synthase but no activity and no detectable levels of COX-1 or COX-2. LPS exposure for 3 h caused COX-2 mRNA and protein levels to rise during 8 h together with a large increase in PGI2 synthase activity. In contrast, cytokines lead to only a moderate increase of both PGI2 and PGE2. Specific COX-2 inhibitors completely blocked PGI2 formation but PGE2 synthesis only partially. Unexpectedly, *NO formation remained low over 6-8 h, which may be a reason for the lack of nitration and inhibition of prostacyclin synthase in LPS exposed SMC. Our results can explain the clinical observation of severe hypotension in progressive stages of septic shock as a mechanism to compensate endothelial dysfunction. According to our data, the use of COX-2-specific inhibitors may not be advisable in septic patients. In contrast, administration of COX-1-specific blockers could prevent platelet aggregation during progressed stages of endotoxic shock.
据报道，感染性休克患者体内前列环素（PGI2；以6-酮-PGF1α衡量）水平较高。由于这与我们之前在内皮细胞中发现内毒素（LPS）硝化并抑制PGI2合酶的结果不一致，我们研究了血管平滑肌作为PGI2另一种来源的作用。第1代牛主动脉平滑肌细胞（SMC）含有高水平的PGI2合酶，但无活性，且未检测到COX-1或COX-2水平。暴露于LPS 3小时导致COX-2 mRNA和蛋白水平在8小时内上升，同时PGI2合酶活性大幅增加。相比之下，细胞因子仅导致PGI2和PGE2适度增加。特异性COX-2抑制剂完全阻断了PGI2的形成，但仅部分阻断了PGE2的合成。出乎意料的是，在6-8小时内一氧化氮（NO）的生成仍然很低，这可能是LPS处理的SMC中缺乏PGI2合酶硝化和抑制的原因。我们的结果可以解释感染性休克进展期严重低血压的临床观察结果，这是一种补偿内皮功能障碍的机制。根据我们的数据，在感染患者中使用COX-2特异性抑制剂可能不可取。相比之下，给予COX-1特异性阻滞剂可以预防内毒素休克进展期的血小板聚集。
