Grandel U, Fink L, Blum A, Heep M, Buerke M, Kraemer H J, Mayer K, Bohle R M, Seeger W, Grimminger F, Sibelius U
Department of Internal Medicine, Justus-Liebig-University, Giessen, Germany.
Circulation. 2000 Nov 28;102(22):2758-64. doi: 10.1161/01.cir.102.22.2758.
Although endotoxin (lipopolysaccharides, LPS) is recognized as a mediator of septic cardiodepression, its cardiac effects are still not fully elucidated.
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(2) 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.
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.
尽管内毒素（脂多糖，LPS）被认为是脓毒症性心肌抑制的介质，但其对心脏的影响仍未完全阐明。
用LPS灌注离体大鼠心脏180分钟，90分钟后左心室收缩力下降，而冠状动脉灌注压未受影响。这种心肌抑制与肿瘤坏死因子（TNF）-α释放到灌注液中同时发生，且在实时聚合酶链反应定量检测到心肌TNF-α mRNA上调之前。当LPS与TNF-α抗血清或神经酰胺酶抑制剂N-油酰乙醇胺一起灌注时，心肌抑制被消除。相反，LPS并未增加一氧化氮（NO）的心脏释放。对LPS灌注心脏的免疫组织化学研究显示，组成型（NOSIII）一氧化氮合酶呈阳性染色，而诱导型一氧化氮合酶（NOSII）呈阴性染色。因此，NOSII mRNA水平仅在LPS灌注期即将结束时才开始增加。LPS诱导血栓素（Tx）A2和前列环素的逐步释放以及心肌环氧化酶（Cox）-2 mRNA表达。吲哚美辛对Cox的非选择性抑制和NS-398对诱导型Cox-2的选择性抑制均消除了前列腺素的释放。有趣的是，吲哚美辛、NS-398和Tx受体拮抗剂达曲班降低了LPS引起的TNF-α生成及相关的心肌抑制。
LPS通过诱导TNF-α合成并随后激活鞘磷脂酶途径来抑制离体大鼠心脏的收缩力，而未发现NOSII或NOSIII生成的NO起作用的证据。此外，Cox-2衍生的TxA2似乎在对LPS的反应中促进TNF-α合成。
