Soluble Epoxide Hydrolase Inhibitor Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Improves Survival in Mice.
Soluble Epoxide Hydrolase Inhibitor Attenuates Lipopolysaccharide-Induced Acute Lung Injury and Improves Survival in Mice.
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可溶性环氧化物水解酶抑制剂可减轻脂多糖引起的急性肺损伤并提高小鼠的存活率
DOI：
10.1097/shk.0000000000000767
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发表时间：
2017-05
期刊：
影响因子：
--
通讯作者：
Guan CX
中科院分区：
文献类型：
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作者：
Zhou Y;Liu T;Duan JX;Li P;Sun GY;Liu YP;Zhang J;Dong L;Lee KSS;Hammock BD;Jiang JX;Guan CX
摘要急性肺损伤（ALI）是以肺泡迅速损伤、血管渗漏、肺部炎症、中性粒细胞聚集和诱导的细胞因子产生导致肺水肿为特征的。ALI患者的死亡率仍然很高。环氧二十碳三烯酸（EETs）是多不饱和脂肪酸的细胞色素P450依赖性衍生物，具有抗高血压、促纤溶和抗炎功能。雌二醇通过可溶性环氧化物水解酶（sEH）快速水合成其较低效力的二醇。本研究旨在探讨sEH抑制剂三氟甲氧基苯基丙酰哌啶脲（TPPU）和依那普利在脂多糖（LPS）诱导的小鼠急性肺损伤（ALI）中的作用。我们的研究表明，TPPU抑制sEH减轻小鼠的形态学改变，减少中性粒细胞浸润到肺，血清和支气管肺泡灌洗液（BALF）中的促炎细胞因子（IL-1和TNF-α）水平，以及肺泡毛细血管渗漏（肺湿/干比和BALF中总蛋白浓度）。TPPU可提高LPS诱导的ALI小鼠的存活率。体外实验表明，TPPU和EET（11，12-EET和14，15-EET）均能抑制RAW264.7细胞IL-1、TNF-α的表达和LDH的释放。这些结果表明，EH在抑制LPS诱导的急性肺部炎症中发挥作用，并表明sEH可能是治疗ALI的有价值的候选者。
ABSTRACT Acute lung injury (ALI) is characterized by rapid alveolar injury, vascular leakage, lung inflammation, neutrophil accumulation, and induced cytokines production leading to lung edema. The mortality rate of patients suffering from ALI remains high. Epoxyeicosatrienoic acids (EETs) are cytochrome P450-dependent derivatives of polyunsaturated fatty acid with antihypertensive, profibrinolytic, and anti-inflammatory functions. EETs are rapidly hydrated by soluble epoxide hydrolase (sEH) to their less potent diols. The aim of this study was to investigate the role of sEH inhibitor trifluoromethoxyphenyl propionylpiperidin urea (TPPU) and EETs in lipopolysaccharide (LPS)-induced ALI of mice. Our studies revealed that inhibition of sEH with TPPU attenuated the morphological changes in mice, decreased the neutrophil infiltration to the lung, pro-inflammatory cytokine levels (IL-1&bgr; and TNF-&agr;) in serum and bronchoalveolar lavage fluid (BALF), and alveolar capillary leakage (lung wet/dry ratio and total protein concentration in BALF). TPPU improved the survival rate of LPS-induced ALI. In addition, in vitro experiments revealed that both TPPU and EETs (11,12-EET and 14,15-EET) suppressed the expression of IL-1&bgr; and TNF-&agr;, and LDH release in RAW264.7 cells. These results indicate that EETs play a role in dampening LPS-induced acute lung inflammation, and suggest that sEH could be a valuable candidate for the treatment of ALI.