Center for Research on Environmental Disease, University of Kentucky, Lexington, KY 40536, USA.
Center for Biomedical Research, University of Texas Health Science Center at Tyler, Tyler, TX 75708, USA.
Toxicol Appl Pharmacol. 2014 Jun 1;277(2):118-23. doi: 10.1016/j.taap.2014.03.017. Epub 2014 Apr 4.
The presence of endotoxin in blood can lead to acute kidney injury (AKI) and septic shock. Resolvins, the endogenous lipid mediators derived from docosahexaenoic acid, have been reported to exhibit potent anti-inflammatory action. Using a mouse model of lipopolysaccharide (LPS)-induced AKI, we investigated the effects of aspirin-triggered resolvin D1 (AT-RvD1) on inflammatory kidney injury. Administration of AT-RvD1 1h after LPS challenge protected the mice from kidney injury as indicated by the measurements of blood urea nitrogen, serum creatinine, and morphological alterations associated with tubular damage. The protective effects were evidenced by decreased neutrophil infiltration in the kidney indicating reduction in inflammation. AT-RvD1 treatment restored kidney cell junction protein claudin-4 expression, which was otherwise reduced after LPS challenge. AT-RvD1 treatment inhibited endotoxin-induced NF-κB activation and suppressed LPS-induced ICAM-1 and VCAM-1 expression in the kidney. Moreover, AT-RvD1 treatment markedly decreased LPS-induced IL-6 level in the kidney and blocked IL-6-mediated signaling including STAT3 and ERK phosphorylation. Our findings demonstrate that AT-RvD1 is a potent anti-inflammatory mediator in LPS-induced kidney injury, and AT-RvD1 has therapeutic potential against AKI during endotoxemia.
内毒素血症可导致急性肾损伤（AKI）和感染性休克。内源性脂质介质(resolvins)，来源于二十二碳六烯酸(DHA)，已被报道具有强大的抗炎作用。我们使用脂多糖（LPS）诱导的 AKI 小鼠模型，研究了阿司匹林触发的 resolvin D1（AT-RvD1）对炎症性肾损伤的影响。在 LPS 攻击后 1 小时给予 AT-RvD1 可保护小鼠免受肾损伤，这可通过测量血尿素氮、血清肌酐和与肾小管损伤相关的形态改变来证实。这种保护作用的证据是肾脏中中性粒细胞浸润减少，表明炎症减少。AT-RvD1 治疗恢复了肾脏细胞连接蛋白 Claudin-4 的表达，而 Claudin-4 的表达在 LPS 攻击后减少。AT-RvD1 治疗抑制了 LPS 诱导的 NF-κB 激活，并抑制了 LPS 诱导的肾脏中 ICAM-1 和 VCAM-1 的表达。此外，AT-RvD1 治疗可显著降低 LPS 诱导的肾脏中 IL-6 水平，并阻断了 IL-6 介导的信号通路，包括 STAT3 和 ERK 磷酸化。我们的研究结果表明，AT-RvD1 是 LPS 诱导的肾损伤中的一种有效的抗炎介质，AT-RvD1 对脓毒症期间的 AKI 具有治疗潜力。
