Original Contribution
Modulation of arachidonic and linoleic acid metabolites in myeloperoxidase-deficient mice during acute inflammation

https://doi.org/10.1016/j.freeradbiomed.2010.02.010Get rights and content

Abstract

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.

Section snippets

Materials

The following AA and LA metabolites were purchased from Cayman Chemicals (Ann Arbor, MI, USA): (±)9(10)-epoxy-12Z-octadecenoic acid [9(10)-EpOME], (±)12(13)-epoxy-9Z-octadecenoic acid [12(13)-EpOME], (±)5(6)-epoxy-8Z,11Z,14Z-eicosatrienoic acid [5(6)-EET)], (±)8(9)-epoxy-5Z,11Z,14Z-eicosatrienoic acid [8(9)-EET], (±)14(15)-epoxy-5Z,8Z,11Z-eicosatrienoic acid [14(15)-EET], (±)11(12)-epoxy-5Z,8Z,14Z-eicosatrienoic acid [11(12)-EET], (±)13-hydroxy-9Z,11E-octadecadienoic acid (13-HODE),

MPO deficiency suppresses endotoxemia-induced formation of LA epoxides and vicinal dihydroxy metabolites of AA and LA

To model acute inflammation associated with systemic endotoxemia/sepsis, we injected mice ip with LPS and measured AA and LA metabolites 24 h later. In wild-type animals, LPS-induced endotoxemia greatly increased the plasma levels of LA epoxides (EpOMEs) as well as vicinal dihydroxy metabolites of AA and LA (DHETEs and DHOMEs, respectively), confirming that the P450-epoxygenase/soluble epoxide hydrolase lipid metabolism pathways are activated in our noninfectious model of systemic sepsis (Table

Discussion

Our results illustrate the significance of MPO in the formation of biologically active metabolites of AA and LA. Data suggest that during acute inflammation, MPO plays an important role in the formation of AA and LA epoxides and hydroxy intermediates together with the catabolism of cysteinyl-LTs. Accordingly, the formation of AA and LA lipid mediators (HETEs, HODEs, and H(P)ODEs) was suppressed in MPO-KO mice and PMNs isolated from these animals. Interestingly, the difference between AA and LA

Acknowledgments

This work was supported by a postdoctoral fellowship from Philip Morris USA, Inc., and Philip Morris International (to L.K.); grants from The Academy of Sciences of the Czech Republic, M200040908, AV0Z50040507, and AV0Z50040702 (to L.K.); a University of California at Davis Health Systems Research Award (to J.P.E.); and the Paul F. Gulyassy Endowed Professorship (to J.P.E.). K.S. received the John Kinsella Dissertation Award and was supported by an NIEHS Training Grant in Environmental

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