Hagn Gerhard, Bileck Andrea, Mohr Thomas, Schmidl Doreen, Baron David M, Jilma Bernd, Schmetterer Leopold, Garhöfer Gerhard, Gerner Christopher
Department of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Waehringer Straße 38, 1090 Vienna, Austria.
Vienna Doctoral School in Chemistry (DoSChem), University of Vienna, Waehringer Straße 42, 1090 Vienna, Austria.
Antioxidants (Basel). 2025 Apr 29;14(5):536. doi: 10.3390/antiox14050536.
Systemic molecular responses to pathogen-associated molecular patterns and their modulation by antioxidants are poorly understood in humans. Here, we present a two-stage clinical interventional study in healthy humans challenged with lipopolysaccharide. In the first step, the kinetics of inflammatory modulators within 8 h were investigated by plasma proteomics and lipidomics. In a second step, the effects of a placebo-controlled antioxidant intervention on the individual responses prior to another lipopolysaccharide challenge were determined. Plasma proteomics revealed an early involvement of the endothelium and platelets, followed by the induction of liver-derived acute phase proteins and an innate immune cell response. Untargeted lipidomics revealed an early release of fatty acids and taurocholic acid, followed by complex regulatory events exerted by oxylipins. The consistent lipopolysaccharide-induced downregulation of lysophospholipids suggested the involvement of the Lands cycle, and the downregulation of deoxycholic acid reinforced emerging links between the inflammasome and bile acids. Groups of molecules with similar kinetics to lipopolysaccharide challenge were observed to share precursors, synthesizing enzymes or cellular origin. Dietary antioxidant supplementation prior to lipopolysaccharide challenge had no detectable effect on protein kinetics but significantly downregulated pro-inflammatory sphingosine-1-phosphate and increased levels of oxylipins, 20-HEPE, and 22-HDoHE, which have been described to facilitate the resolution of inflammation. The present study identified a complex network of lipid mediators deregulated in plasma upon lipopolysaccharide challenge and highlighted the role of platelets, endothelial cells, and erythrocytes as potential inflammatory modulators. While dietary antioxidant supplementation hardly affected the initiation of inflammation, it may exert its effects supporting the resolution of inflammation.
在人类中，对病原体相关分子模式的全身分子反应及其被抗氧化剂调节的情况尚不清楚。在此，我们展示了一项针对健康人进行的两阶段临床干预研究，这些健康人接受了脂多糖刺激。第一步，通过血浆蛋白质组学和脂质组学研究8小时内炎症调节因子的动力学。第二步，确定在另一次脂多糖刺激之前，安慰剂对照的抗氧化剂干预对个体反应的影响。血浆蛋白质组学显示内皮细胞和血小板早期参与，随后诱导肝脏衍生的急性期蛋白和先天性免疫细胞反应。非靶向脂质组学显示脂肪酸和牛磺胆酸早期释放，随后是氧化脂质发挥的复杂调节事件。脂多糖一致诱导的溶血磷脂下调表明Lands循环参与其中，脱氧胆酸的下调加强了炎症小体和胆汁酸之间新出现的联系。观察到与脂多糖刺激动力学相似的分子组共享前体、合成酶或细胞来源。在脂多糖刺激之前补充膳食抗氧化剂对蛋白质动力学没有可检测到的影响，但显著下调促炎鞘氨醇-1-磷酸，并增加氧化脂质、20-HEPE和22-HDoHE的水平，这些物质已被描述为有助于炎症的消退。本研究确定了脂多糖刺激后血浆中失调的脂质介质复杂网络，并强调了血小板、内皮细胞和红细胞作为潜在炎症调节因子的作用。虽然膳食抗氧化剂补充几乎不影响炎症的启动，但它可能发挥支持炎症消退的作用。
