Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress.

BACKGROUND AND PURPOSE: Inflammation is associated with oxidative stress and local generation of lipid peroxidation-derived aldehydes, such as 4-hydroxy-trans-2-nonenal (HNE). In most tissues, HNE is readily conjugated with glutathione and presently it is unknown whether glutathionyl-HNE (GS-HNE) plays a functional role in inflammation. Here, we sought to determine whether GS-HNE is a mediator of oxidative stress-initiated inflammation and if its actions can be regulated by the anti-inflammatory and pro-resolving lipid mediator, resolvin D1 (RvD1). EXPERIMENTAL APPROACH: GS-HNE was administered intraperitoneally to mice and peritoneal lavages were assessed for leukocyte infiltration and lipid mediators were targeted by mediator-lipidomics. RvD1 was administered to mice treated with GS-HNE and leukocyte infiltration was assessed in the peritoneum. Superoxide production and CD11b modulation were measured in isolated human polymorphonuclear leukocytes incubated with GS-HNE. KEY RESULTS: GS-HNE (1-10 microg) evoked infiltration of Gr-1(+) leukocytes into the peritoneum to form an inflammatory exudate. With isolated human polymorphonuclear leukocytes, GS-HNE stimulated both superoxide generation and CD11b expression. Among the lipid mediators, both cyclooxygenase- and lipoxygenase-derived pro-inflammatory eicosanoids, including prostaglandin E(2), leukotriene B(4) and cysteinyl leukotrienes, were generated in exudates of mice injected intraperitoneally with GS-HNE. RvD1, given i.v. in doses as low as 0.01-10.0 ng, sharply reduced GS-HNE-stimulated leukocyte infiltration ( approximately 30-70%). CONCLUSIONS AND IMPLICATIONS: Glutathione conjugates of HNE, derived during oxidative stress, are pro-inflammatory in vivo. RvD1 protects against this oxidative stress-initiated inflammation.