Endotoxin-induced myocardial tumor necrosis factor-α synthesis depresses contractility of isolated rat hearts -: Evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production
Endotoxin-induced myocardial tumor necrosis factor-α synthesis depresses contractility of isolated rat hearts -: Evidence for a role of sphingosine and cyclooxygenase-2-derived thromboxane production
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DOI：
10.1161/01.cir.102.22.2758
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发表时间：
2000-11-28
期刊：
影响因子：
37.8
通讯作者：
Sibelius, U
中科院分区：
文献类型：
--
作者：
Grandel, U;Fink, L;Sibelius, U
背景-尽管内毒素(脂多糖)被认为是感染性心脏抑制的媒介，但其心脏作用仍不完全清楚。方法和结果：用内毒素灌流大鼠离体心180分钟后，左心室收缩功能在90分钟后下降，而冠脉灌流压保持不变。这种心脏抑制与肿瘤坏死因子(TNF)-α释放到灌流液中平行，并在此之前通过实时聚合酶链式反应(RT-PCR)定量检测心肌组织中肿瘤坏死因子-α的mRNA表达上调。当用肿瘤坏死因子-α抗血清或神经酰胺酶抑制剂N-油酰乙醇胺灌流内毒素时，心脏抑制作用被解除。相反，内毒素不能增加心脏一氧化氮(NO)的释放。对脂多糖灌流心脏的免疫组织化学研究显示，组成成分(NOSIII)呈阳性染色，而诱导型一氧化氮合酶(NOSII)则不呈阳性染色。因此，NOSII基因的水平只有在脂多糖灌注期结束时才开始增加。内毒素诱导血栓烷(Tx)A和前列环素(PGI)逐渐释放，并伴有心肌环氧合酶(COX)-2mRNA的表达。消炎痛对COX的非选择性抑制和NS-398选择性抑制诱导型COX-2均可阻断前列腺素释放。有趣的是，消炎痛、NS-398和TX受体拮抗剂达曲班均可减少内毒素引起的肿瘤坏死因子-α的产生和相关的心脏抑制。结论-内毒素通过诱导肿瘤坏死因子-α的合成和随后激活鞘磷脂酶途径抑制大鼠心脏的收缩，而没有证据表明NOSII或NOSIII产生的NO起作用。此外，COX-2衍生的TXA(2)似乎促进了肿瘤坏死因子-α的合成，以应对内毒素。
Background-Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated.Methods and Results-Perfusion of isolated rat hearts with LPS for 180 minutes resulted in a decline of left ventricular contractility after 90 minutes, whereas coronary perfusion pressure remained unaffected. This cardiodepression was paralleled by a release of tumor necrosis factor (TNF)-alpha into the perfusate and preceded by myocardial TNF-alpha mRNA upregulation as quantified by real-time polymerase chain reaction. The cardiodepression was abrogated when LPS was perfused with a TNF-alpha antiserum or the ceramidase inhibitor N-oleoylethanolamine. In contrast, the cardiac release of nitric oxide (NO) was not augmented by LPS. Immunohistochemical studies of LPS-perfused hearts revealed a positive staining for the constitutive (NOSIII) but not for the inducible NO synthase (NOSII). Accordingly, NOSII mRNA levels commenced to increase only at the very end of the LPS perfusion period. Progressive liberation of thromboxane(Tx) A, and prostacyclin was induced by LPS together with myocardial cyclooxygenase (Cox)-2 mRNA expression. Both nonselective inhibition of Cox by indomethacin and selective inhibition of the inducible Cox-2 by NS-398 abolished prostanoid release. Interestingly, the generation of TNF-alpha and the associated cardiodepression caused by LPS were reduced by indomethacin, NS-398 and the Tx-receptor antagonist daltroban.Conclusions-LPS depresses contractility of isolated rat hearts by inducing TNF-alpha synthesis and subsequently activating the sphingomyelinase pathway, whereas no evidence for a role of NOSII- or NOSIII-generated NO was found. Moreover, Cox-2-derived TxA(2) appears to facilitate TNF-alpha synthesis in response to LPS.