Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.

摘要: Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or 5-LOX-activating protein (FLAP). These related enzymes act in conjunction marked crosstalk within a complex lipid mediator (LM) network where also specialized proresolving LMs (SPMs) are formed. Here, we present how prominent LM pathways can be differentially modulated human M1 M2 macrophage phenotypes that, upon exposure Escherichia coli, produce either abundant (M1) SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied analyze quantify specific profiles. Besides expected on-target actions, found that: 1) COX 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, 2) FLAP 5-LOX reduce but less so macrophages, 3) zileuton blocks resolution-initiating SPM biosynthesis, whereas inhibition increases 4) that inhibitor 3887 suppresses formation macrophages. Conclusively, interference discrete biosynthetic different considerably affects metabolomes potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal therapeutic these intervene disorders.-Werner, M., Jordan, P. Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting networks metabolome.