Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep
Renal effects of treatment with a TLR4 inhibitor in conscious septic sheep
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DOI：
10.1186/s13054-014-0488-y
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发表时间：
2014-01-01
期刊：
影响因子：
15.1
通讯作者：
Frithiof, Robert
中科院分区：
文献类型：
--
作者：
Fenhammar, Johan;Rundgren, Mats;Frithiof, Robert
前言：急性肾损伤(AKI)是脓毒症常见且令人畏惧的并发症。脓毒症所致AKI的发病机制目前尚不清楚，治疗干预主要是支持性的。在本研究中，我们验证了这样的假设，即药物抑制Toll样受体4(TLR4)可以改善实验性脓毒症的肾功能，减少肾损害，即使在AKI已经形成之后。12小时后，随机接受选择性TLR4抑制剂(TAK-242)或赋形剂的治疗。结果：大肠埃希菌引起正常血压脓毒症，以发热、心脏指数增加、高乳酸血症、少尿和肌酐清除率下降为特征。Tak-242显著改善了内生肌酐清除率和尿量。肾小管损伤的标志物N-乙酰-β-D-氨基葡萄糖苷的增加有所减弱。此外，TAK-242还可减轻脓毒症所致的肾中性粒细胞积聚和肾小球内皮细胞肿胀。这些效应与肾动脉血流和肾皮质和髓质微血管灌注量的变化无关。Tak-242本身对测量的参数没有影响。结论：这些结果表明，TLR4抑制剂治疗能够逆转脓毒症引起的明显的肾功能损害。此外，这些结果提供了证据表明，TAK-242对肾功能的影响机制不涉及改善大循环或微循环，增加肾脏氧输送，或减轻肾小管坏死。TLR4介导的炎症导致肾小球内皮细胞肿胀可能是革兰氏阴性败血症急性肾损伤发病机制的重要组成部分。
Introduction: Acute kidney injury (AKI) is a common and feared complication of sepsis. The pathogenesis of sepsis-induced AKI is largely unknown, and therapeutic interventions are mainly supportive. In the present study, we tested the hypothesis that pharmacological inhibition of Toll-like receptor 4 (TLR4) would improve renal function and reduce renal damage in experimental sepsis, even after AKI had already developed.Methods: Sheep were surgically instrumented and subjected to a 36-hour intravenous infusion of live Escherichia coli. After 12 hours, they were randomized to treatment with a selective TLR4 inhibitor (TAK-242) or vehicle.Results: The E. coli caused normotensive sepsis characterized by fever, increased cardiac index, hyperlactemia, oliguria, and decreased creatinine clearance. TAK-242 significantly improved creatinine clearance and urine output. The increase in N-acetyl-beta-D-glucosaminidas, a marker of tubular damage, was attenuated. Furthermore, TAK-242 reduced the renal neutrophil accumulation and glomerular endothelial swelling caused by sepsis. These effects were independent of changes in renal artery blood flow and renal microvascular perfusion in both cortex and medulla. TAK-242 had no effect per se on the measured parameters.Conclusions: These results show that treatment with a TLR4 inhibitor is able to reverse a manifest impairment in renal function caused by sepsis. In addition, the results provide evidence that the mechanism underlying the effect of TAK-242 on renal function does not involve improved macro-circulation or micro-circulation, enhanced renal oxygen delivery, or attenuation of tubular necrosis. TLR4-mediated inflammation resulting in glomerular endothelial swelling may be an important part of the pathogenesis underlying Gram-negative septic acute kidney injury.