THEMED SECTION: MEDIATORS AND RECEPTORS IN THE RESOLUTION OF INFLAMMATION. RESEARCH PAPER
Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress
Article first published online: 5 MAY 2009
© 2009 The Authors. Journal compilation © 2009 The British Pharmacological Society
British Journal of Pharmacology
Special Issue: Themed Section: Mediators and Receptors in the Resolution of Inflammation: Guest Editor: AG Stewart
Volume 158, Issue 4, pages 1062–1073, October 2009
How to Cite
Spite, M., Summers, L., Porter, T., Srivastava, S., Bhatnagar, A. and Serhan, C. (2009), Resolvin D1 controls inflammation initiated by glutathione-lipid conjugates formed during oxidative stress. British Journal of Pharmacology, 158: 1062–1073. doi: 10.1111/j.1476-5381.2009.00234.x
- Issue published online: 16 OCT 2009
- Article first published online: 5 MAY 2009
- Received 22 December 2008; accepted 15 January 2009
- lipid mediators;
- 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 µg) 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 E2, leukotriene B4 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 (∼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.
This article is part of a themed issue on Mediators and Receptors in the Resolution of Inflammation. To view this issue visit http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009