Center for Nephrology & Metabolomics, Division of Nephrology & Rheumatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, China.
Rheumatology (Oxford). 2019 Feb 1;58(2):345-351. doi: 10.1093/rheumatology/key284.
Monosodium urate-induced inflammation plays a vital role in acute gout (AG). Inflammation is a multi-stage process involved in the acute release of arachidonic acid and its metabolites. However, the function of the metabolism of arachidonic acid and other polyunsaturated fatty acids in AG is not well understood. This study aimed to investigate the modification of polyunsaturated fatty acid metabolism by AG.
Plasma samples from patients with an AG attack (n = 26) and gender-matched healthy controls (n = 26) were analysed by metabolic profiling of polyunsaturated fatty acids. The findings were further validated with a second cohort (n = 20 each group). The associated mechanisms were investigated in whole blood cells from the second cohort and neutrophils in vitro.
Plasma metabolic profiling revealed a significant increase in leukotriene B4 (LTB4) for AG patients in both cohorts. The increase in plasma LTB4 was accounted for by the dynamic balance between the activation of 5-lipoxygenase and CYP4F3, the former mediating the biosynthesis of LTB4 and the latter mediating its metabolism. This was supported by significantly increased transcriptional levels of 5-lipoxygenase and CYP4F3 in whole blood cells from AG patients compared with those of controls, and the uric acid-caused dose-relevant and time-dependent activation of 5-lipoxygenase and CYP4F3 at the transcriptional and molecular levels in vitro.
Increased LTB4 in AG patients is mainly due to activation of 5-lipoxygenase. 5-Lipoxygenase inhibition may be of therapeutic value clinically.
尿酸单钠诱导的炎症在急性痛风（AG）中起着至关重要的作用。炎症是一个多阶段的过程，涉及花生四烯酸及其代谢物的急性释放。然而，AG 中花生四烯酸和其他多不饱和脂肪酸代谢的功能尚不清楚。本研究旨在探讨 AG 对多不饱和脂肪酸代谢的修饰。
通过多不饱和脂肪酸代谢组学分析 AG 发作患者（n=26）和性别匹配的健康对照者（n=26）的血浆样本。在第二个队列（每组 n=20）中进一步验证了这些发现。在第二个队列的全血细胞和体外中性粒细胞中研究了相关机制。
血浆代谢组学分析显示，两个队列的 AG 患者白细胞三烯 B4（LTB4）显著增加。血浆 LTB4 的增加是由于 5-脂氧合酶和 CYP4F3 的激活之间的动态平衡，前者介导 LTB4 的生物合成，后者介导其代谢。这得到了以下证据的支持：与对照组相比，AG 患者的全血细胞中 5-脂氧合酶和 CYP4F3 的转录水平显著增加，尿酸在体外引起的 5-脂氧合酶和 CYP4F3 的转录和分子水平的剂量相关和时间依赖性激活。
AG 患者中 LTB4 的增加主要归因于 5-脂氧合酶的激活。5-脂氧合酶抑制在临床上可能具有治疗价值。
