Department of Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Friedrich Schiller University Jena, Jena, Germany.
Division of Hematology, Department of Medicine, Karolinska University Hospital Solna, Stockholm, Sweden.
FASEB J. 2019 May;33(5):6140-6153. doi: 10.1096/fj.201802509R. Epub 2019 Feb 8.
Nonsteroidal anti-inflammatory drugs interfere with the metabolism of arachidonic acid to proinflammatory prostaglandins and leukotrienes by targeting cyclooxygenases (COXs), 5-lipoxygenase (LOX), or the 5-LOX-activating protein (FLAP). These and related enzymes act in conjunction with 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 in human proinflammatory M1 and proresolving M2 macrophage phenotypes that, upon exposure to , produce either abundant prostaglandins and leukotrienes (M1) or SPMs (M2). Targeted liquid chromatography-tandem mass spectrometry-based metabololipidomics was applied to analyze and quantify the specific LM profiles. Besides expected on-target actions, we found that: ) COX or 15-LOX-1 inhibitors elevate inflammatory leukotriene levels, ) FLAP and 5-LOX inhibitors reduce leukotrienes in M1 but less so in M2 macrophages, ) zileuton blocks resolution-initiating SPM biosynthesis, whereas FLAP inhibition increases SPM levels, and ) that the 15-LOX-1 inhibitor 3887 suppresses SPM formation in M2 macrophages. Conclusively, interference with discrete LM biosynthetic enzymes in different macrophage phenotypes considerably affects the LM metabolomes with potential consequences for inflammation-resolution pharmacotherapy. Our data may allow better appraisal of the therapeutic potential of these drugs to intervene with inflammatory disorders.-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. Targeting biosynthetic networks of the proinflammatory and proresolving lipid metabolome.
非甾体抗炎药通过靶向环氧化酶 (COX)、5-脂氧合酶 (LOX) 或 5-LOX 激活蛋白 (FLAP) 来干扰花生四烯酸代谢为促炎前列腺素和白三烯。这些和相关的酶与复杂脂质介质 (LM) 网络中的显著串扰一起作用，其中还形成了专门的促解决 LM (SPM)。在这里，我们展示了在人类促炎 M1 和促解决 M2 巨噬细胞表型中，如何差异化调节突出的 LM 途径，这些表型在暴露于 后，产生大量前列腺素和白三烯 (M1) 或 SPM (M2)。应用靶向液相色谱-串联质谱法代谢脂质组学分析和定量特定的 LM 谱。除了预期的靶向作用外，我们还发现：) COX 或 15-LOX-1 抑制剂可提高炎症性白三烯水平，) FLAP 和 5-LOX 抑制剂减少 M1 中的白三烯，但在 M2 巨噬细胞中减少较少，) zileuton 阻断起始 SPM 生物合成，而 FLAP 抑制增加 SPM 水平，以及) 15-LOX-1 抑制剂 3887 抑制 M2 巨噬细胞中 SPM 的形成。总之，在不同的巨噬细胞表型中干扰离散的 LM 生物合成酶会显著影响 LM 代谢组，这可能对炎症缓解的药物治疗有潜在影响。我们的数据可能有助于更好地评估这些药物的治疗潜力，以干预炎症性疾病。-Werner, M., Jordan, P. M., Romp, E., Czapka, A., Rao, Z., Kretzer, C., Koeberle, A., Garscha, U., Pace, S., Claesson, H.-E., Serhan, C. N., Werz, O., Gerstmeier, J. 靶向促炎和促解决脂质代谢组的生物合成网络。
