Department of Internal Medicine, University of California at Davis, Davis, CA 95616, USA.
Free Radic Biol Med. 2010 May 15;48(10):1311-20. doi: 10.1016/j.freeradbiomed.2010.02.010. Epub 2010 Feb 13.
Acute inflammation is a common feature of many life-threatening pathologies, including septic shock. One hallmark of acute inflammation is the peroxidation of polyunsaturated fatty acids forming bioactive products that regulate inflammation. Myeloperoxidase (MPO) is an abundant phagocyte-derived hemoprotein released during phagocyte activation. Here, we investigated the role of MPO in modulating biologically active arachidonic acid (AA) and linoleic acid (LA) metabolites during acute inflammation. Wild-type and MPO-knockout (KO) mice were exposed to intraperitoneally injected endotoxin for 24 h, and plasma LA and AA oxidation products were comprehensively analyzed using a liquid chromatography-mass spectrometry method. Compared to wild-type mice, MPO-KO mice had significantly lower plasma levels of LA epoxides and corresponding LA- and AA-derived fatty acid diols. AA and LA hydroxy intermediates (hydroxyeicosatetraenoic and hydroxyoctadecadienoic acids) were also significantly lower in MPO-KO mice. Conversely, MPO-deficient mice had significantly higher plasma levels of cysteinyl-leukotrienes with well-known proinflammatory properties. In vitro experiments revealed significantly lower amounts of AA and LA epoxides, LA- and AA-derived fatty acid diols, and AA and LA hydroxy intermediates in stimulated polymorphonuclear neutrophils isolated from MPO-KO mice. Our results demonstrate that MPO modulates the balance of pro- and anti-inflammatory lipid mediators during acute inflammation and, in this way, may control acute inflammatory diseases.
急性炎症是许多危及生命的病理学的共同特征，包括感染性休克。急性炎症的一个标志是多不饱和脂肪酸的过氧化，形成调节炎症的生物活性产物。髓过氧化物酶（MPO）是一种丰富的吞噬细胞衍生的血红蛋白，在吞噬细胞激活时释放。在这里，我们研究了 MPO 在调节急性炎症期间生物活性花生四烯酸（AA）和亚油酸（LA）代谢物中的作用。野生型和 MPO 敲除（KO）小鼠接受腹腔内注射内毒素 24 小时，并用液相色谱-质谱法全面分析血浆 LA 和 AA 氧化产物。与野生型小鼠相比，MPO-KO 小鼠的血浆 LA 环氧化物和相应的 LA 和 AA 衍生脂肪酸二醇水平显著降低。AA 和 LA 羟基中间体（羟二十碳四烯酸和羟十八碳二烯酸）在 MPO-KO 小鼠中也显著降低。相反，缺乏 MPO 的小鼠的半胱氨酰白三烯水平显著升高，半胱氨酰白三烯具有众所周知的促炎特性。体外实验表明，从 MPO-KO 小鼠分离的刺激多形核白细胞中 AA 和 LA 环氧化物、LA 和 AA 衍生脂肪酸二醇以及 AA 和 LA 羟基中间体的含量明显降低。我们的结果表明，MPO 在急性炎症期间调节促炎和抗炎脂质介质的平衡，并以此方式控制急性炎症性疾病。
