Modulation of arachidonic and linoleic acid metabolites in myeloperoxidase-deficient mice during acute inflammation.
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.
Kubala
Lukas
L
Department of Internal Medicine, University of California at Davis, Davis, CA 95616, USA. kubalal@ibp.cz
Schmelzer
Kara R
KR
Klinke
Anna
A
Kolarova
Hana
H
Baldus
Stephan
S
Hammock
Bruce D
BD
Eiserich
Jason P
JP
D000818:Animals; D016718:Arachidonic Acid / Q000378:metabolism*; D002853:Chromatography, Liquid; D004195:Disease Models, Animal; D004852:Epoxy Compounds / Q000097:blood; D005231:Fatty Acids, Unsaturated / Q000097:blood; D006893:Hydroxyeicosatetraenoic Acids / Q000097:blood; D007249:Inflammation; D019787:Linoleic Acid / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000008:administration & dosage; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000378:metabolism* / Q000473:pathology; D009195:Peroxidase / Q000235:genetics*; D012772:Shock, Septic / Q000097:blood / Q000378:metabolism*
D004852:Epoxy Compounds; D005231:Fatty Acids, Unsaturated; D006893:Hydroxyeicosatetraenoic Acids; D008070:Lipopolysaccharides; C495366:hydroxyoctadecadienoic acid; D016718:Arachidonic Acid; D019787:Linoleic Acid; D009195:Peroxidase