A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinfiammatory mediator, high mobility group box 1
A cardiovascular drug rescues mice from lethal sepsis by selectively attenuating a late-acting proinfiammatory mediator, high mobility group box 1
复制标题
DOI：
10.4049/jimmunol.178.6.3856
复制
发表时间：
2007-03-15
影响因子：
4.4
通讯作者：
Wang, Haichao
中科院分区：
文献类型：
--
作者：
Li, Wei;Li, Jianhua;Wang, Haichao
脓毒症的发病机制部分由细菌内毒素介导，内毒素刺激巨噬细胞/单核细胞依次释放早期（如肿瘤坏死因子、白细胞介素 - 1和干扰素 - γ）和晚期（如高迁移率族蛋白B1（HMGB1））促炎细胞因子。近期发现HMGB1是致命性脓毒症的一种晚期介质，这促使人们开展新的实验性治疗方法的研究。我们发现许多甾体类药物（如地塞米松和可的松）以及非甾体类抗炎药（如阿司匹林、布洛芬和吲哚美辛）即使在超药理浓度（高达10 - 25 μM）下也无法影响内毒素诱导的HMGB1释放。然而，一种常用中药丹参（Salvia miltiorrhiza）的几种类固醇样色素（丹参酮I、丹参酮IIA和隐丹参酮）在巨噬细胞/单核细胞培养中呈剂量依赖性地减弱内毒素诱导的HMGB1释放。一种水溶性的丹参酮IIA磺酸钠衍生物（TSNIIA - SS）已广泛用作心血管疾病患者的中药，它以不依赖糖皮质激素受体的方式选择性地消除内毒素诱导的HMGB1胞质转位和释放。给予TSNIIA - SS可显著保护小鼠免受致命性内毒素血症的侵害，并且即使在脓毒症发作24小时后给予第一剂，也能使小鼠从致命性脓毒症中获救。治疗效果部分归因于脓毒症动物体内HMGB1（而非肿瘤坏死因子和一氧化氮）全身蓄积的减少以及心血管生理参数的改善（如外周血管总阻力降低和心搏量增加）。综上所述，这些数据强化了HMGB1在致命性脓毒症中的致病作用，并支持TSNIIA - SS在人类脓毒症治疗中的潜在治疗价值。
The pathogenesis of sepsis is mediated in part by bacterial endotoxin, which stimulates macrophages/monocytes to sequentially release early (e.g., TNF, IL-1, and IFN-gamma) and late (e.g., high mobility group box 1 (HMGB1) protein) proinflammatory cytokines. The recent discovery of HMGB1 as a late mediator of lethal sepsis has prompted investigation for development of new experimental therapeutics. We found that many steroidal drugs (such as dexamethasone and cortisone) and nonsteroidal antiinflammatory drugs (such as aspirin, ibuprofen, and indomethacin) failed to influence endotoxin-induced HMGB1 release even at superpharmacological concentrations (up to 10-25 mu M). However, several steroid-like pigments (tanshinone I, tanshinone HA, and cryptotanshinone) of a popular Chinese herb, Danshen (Salvia miltiorrhiza), dose dependently attenuated endotoxin-induced HMGB1 release in macrophage/monocyte cultures. A water-soluble tanshinone HA sodium sulfonate derivative (TSNIIA-SS), which has been widely used as a Chinese medicine for patients with cardiovascular disorders, selectively abrogated endotoxin-induced HMGB1 cytoplasmic translocation and release in a glucocorticoid receptor-independent manner. Administration of TSNIIA-SS significantly protected mice against lethal endotoxemia and rescued mice from lethal sepsis even when the first dose was given 24 h after the onset of sepsis. The therapeutic effects were partly attributable to attenuation of systemic accumulation of HMGB1 (but not TNF and NO) and improvement of cardiovascular physiologic parameters (e.g., decrease in total peripheral vascular resistance and increase in cardiac stroke volume) in septic animals. Taken together, these data re-enforce the pathogenic role of HMGB1 in lethal sepsis, and support a therapeutic potential for TSNIIA-SS in the treatment of human sepsis.