Antioxidative Supplementation Has Minimal Impact on the Initiation of Inflammation but May Instead Facilitate Its Resolution

Systemic molecular responses to pathogen-associated molecular patterns and their modulation via antioxidants have hardly been determined in humans. Here, we present a dual stage clinical interventional study in healthy humans challenged with lipopolysaccharide. In a first stage, the kinetics of inflammatory modulators within eight hours was investigated by plasma proteomics and lipidomics. In a second stage, the effects of a placebo-controlled antioxidative intervention on the individual responses prior to another lipopolysaccharide challenge were determined. Plasma proteomics indicated the 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 demonstrated the early release of fatty acids and taurocholic acid, followed by complex regulatory events exerted by oxylipins. The consistent lipopolysaccharide-induced downregulation of lysophospholipids indicated the involvement of the Lands cycle, and the downregulation of deoxycholic acid reinforced emerging associations between inflammasome and bile acids. Groups of molecules with similar kinetics upon lipopolysaccharide challenge were observed to have common precursors, synthesizing enzymes or cellular origin. Dietary supplementation with antioxidants before the lipopolysaccharide challenge did not detectably affect the kinetics of proteins but significantly downregulated pro-inflammatory sphingosine-1-phosphate and increased the levels of oxylipins described to facilitate the resolution of inflammation, 20-HEPE and 22-HDoHE. The present study identified a complex network of lipids deregulated in plasma upon lipopolysaccharide challenge and highlighted the role of platelets and erythrocytes as potent inflammatory modulators. While dietary antioxidant supplementation had minimal impact on inflammatory responses, it was shown to support the resolution of inflammation.