IN VIVO TOLL-LIKE RECEPTOR 4 ANTAGONISM RESTORES CARDIAC FUNCTION DURING ENDOTOXEMIA
IN VIVO TOLL-LIKE RECEPTOR 4 ANTAGONISM RESTORES CARDIAC FUNCTION DURING ENDOTOXEMIA
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DOI：
10.1097/shk.0b013e318235805f
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发表时间：
2011-12-01
期刊：
影响因子：
3.1
通讯作者：
Knuefermann, Pascal
中科院分区：
文献类型：
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作者：
Ehrentraut, Stefan;Lohner, Ralph;Knuefermann, Pascal
严重的脓毒症和感染性休克常伴有急性心血管抑郁。脂多糖(LPS)通过Toll样受体4(TLR4)信号转导可导致脓毒症器官功能障碍。本研究的目的是阐明药物TLR4拮抗剂对内毒素诱导的心血管抑制的影响。为模拟脓毒症，对C3H/HEN小鼠进行腹腔注射。内毒素2 mg/kg体重。为了对抗脂多糖的影响，对厄立特里亚进行了静脉注射。(4毫克/公斤体重)。记录注射脂多糖和厄立特里亚前后的体力活动、外周血压和心率。此外，使用压力传导导管分析心内血流动力学参数。分别于LPS刺激后2、6h处死大鼠心脏和主动脉，用逆转录定量聚合酶链式反应和酶联免疫吸附试验检测TLR和炎性介质的表达。随着时间的推移，脂多糖显著降低动脉血压。厄立特里亚政府部分阻止了依赖内毒素的血压下降，并保留了心脏功能。此外，脂多糖还可增加心脏和主动脉组织中CD14和TLR2的表达。在主动脉组织中，厄立特里亚减轻了这种增加，而在心脏中没有观察到明显的减少。此外，心肌和主动脉组织中诱导型一氧化氮合酶基因表达水平在注射内毒素后6h显著升高。在厄立特里亚人在场的情况下，这一效果有所减弱。综上所述，厄立特里亚对体内心血管功能的有益影响似乎主要依赖于减少内毒素诱导的诱导型一氧化氮合酶的表达以及血管壁细胞因子的表达。
Severe sepsis and septic shock are often accompanied by acute cardiovascular depression. Lipopolysaccharide (LPS) signaling via Toll-like receptor 4 (TLR4) can induce septic organ dysfunction. The aim of this study was to elucidate the in vivo impact of pharmacological TLR4 antagonism on LPS-induced cardiovascular depression using eritoran tetrasodium (E5564). To simulate sepsis, C3H/HeN mice were challenged i.p. with 2 mg/kg body weight LPS. With the intent to antagonize the LPS effects, eritoran was administered i.v. (4 mg/kg body weight). Physical activity, peripheral blood pressure, and heart frequency were recorded before and after LPS and eritoran injection. In addition, intracardiac hemodynamic parameters were analyzed with a pressure conductance catheter. After 2 and 6 h of LPS stimulation T eritoran treatment, the hearts and aortae were harvested, and TLR as well as inflammatory mediator expression was measured using reverse transcription-quantitative polymerase chain reaction and enzyme-linked immunosorbent assay. Lipopolysaccharide significantly decreased arterial blood pressure over time. Administration of eritoran partially prevented the LPS-dependent reduction in blood pressure and preserved cardiac function. In addition, LPS increased the expression of CD14 and TLR2 in cardiac and aortic tissue. In aortic tissue, eritoran attenuated this increase, whereas no significant reduction was observed in the heart. Furthermore, cardiac and aortic inducible nitric oxide synthetase mRNA levels were significantly increased 6 h after LPS application. This effect was reduced in the presence of eritoran. In summary, the beneficial influence of eritoran on cardiovascular function in vivo seems to rely mainly on reduction of LPS-induced inducible nitric oxide synthetase expression as well as on attenuated cytokine expression in the vascular wall.