Larsson Niklas, McReynolds Cindy B, Hwang Sung Hee, Wan Debin, Yang Jun, Lindberg Richard, Lehtipalo Stefan, Claesson Jonas, Liljeström Amanda Irgum, Lind Alicia, Brolin Anders, Mettävainio Martin Isaksson, Hammock Bruce D, Morisseau Christophe, Nording Malin L
Anesthesiology and Intensive Care, Department of Diagnostics and Intervention, Umeå University, Umeå, Sweden.
Department of Entomology and Nematology, and UC Davis Comprehensive Cancer Center, University of California Davis, Davis, CA, United States.
Front Pharmacol. 2025 Sep 10;16:1652349. doi: 10.3389/fphar.2025.1652349. eCollection 2025.
Pharmacological inhibition of soluble epoxide hydrolase has been shown to attenuate lung injury development in rodents exposed to bacterial lipopolysaccharide. To investigate if these effects can be reproduced in larger animals, we tested soluble epoxide hydrolase (sEH) inhibition using an sEH inhibitor 1-adamantanyl-3-{5-[2-(ethylethoxy)ethoxy]pentyl}urea (AEPU) in a porcine model of lipopolysaccharide-induced acute lung injury. AEPU was selected from 23 sEH inhibitors based on IC50 values and metabolic stability profiles established by a fluorescent based activity assay and porcine liver microsomal test, respectively. Hydrolysis of fatty acid epoxides to their corresponding diols is catalyzed by sEH. Inhibition of sEH reduces this conversion, leading to an accumulation of epoxides relative to diols. Hence, AEPU-treated subjects (n = 9) showed metabolic signs of effective inhibition of the target enzyme reflected in an increased epoxide/diol ratio of 12 (13)-epoxyoctadecenoic acid to 12,13-dihydroxyoctadecenoic acid compared to placebo-treated controls (p = 0.026). However, there was no difference in lung injury development or survival in subjects treated with the rapidly metabolized AEPU compared to placebo-treated controls (n = 10). In conclusion, administration of the soluble epoxide hydrolase inhibitor AEPU did not attenuate endotoxin induced lung injury with lipopolysaccharide in pigs under the severe conditions tested here.
可溶性环氧化物水解酶的药理学抑制已被证明可减轻暴露于细菌脂多糖的啮齿动物的肺损伤发展。为了研究这些效应是否能在更大的动物中重现，我们在脂多糖诱导的急性肺损伤猪模型中使用可溶性环氧化物水解酶（sEH）抑制剂1-金刚烷基-3-{5-[2-(乙基乙氧基)乙氧基]戊基}脲（AEPU）测试了sEH抑制作用。基于分别通过荧光活性测定和猪肝微粒体试验建立的IC50值和代谢稳定性概况，从23种sEH抑制剂中选择了AEPU。脂肪酸环氧化物水解为其相应的二醇是由sEH催化的。抑制sEH可减少这种转化，导致相对于二醇而言环氧化物积累。因此，与安慰剂治疗的对照组相比，AEPU治疗的受试者（n = 9）显示出目标酶有效抑制的代谢迹象，反映为12（13）-环氧十八碳烯酸与12,13-二羟基十八碳烯酸的环氧/二醇比值增加（p = 0.026）。然而，与安慰剂治疗的对照组（n = 10）相比，用快速代谢的AEPU治疗的受试者在肺损伤发展或存活率方面没有差异。总之，在此测试的严峻条件下，给予可溶性环氧化物水解酶抑制剂AEPU并不能减轻猪体内脂多糖诱导的内毒素性肺损伤。
