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New endogenous anti-inflammatory and proresolving lipid mediators: implications for rheumatic diseases

Nature Clinical Practice Rheumatology volume 3, pages 570–579 (2007)Cite this article

Abstract

Prostaglandins and leukotrienes are lipid mediators that carry out pivotal roles in host defense and acute inflammation. Failure to completely resolve an acute inflammatory response can lead to chronic inflammation, scarring, and eventual loss of tissue function. Until recently, it was thought that tissue resolution of acute inflammation was a passive event. However, it is now known than lipoxins, which—like prostaglandins and leukotrienes—are also derived from arachidonic acid, are active anti-inflammatory and proresolution mediators, acting in part by reducing neutrophil entry to the inflammation site and stimulating the uptake of apoptotic polymorphonuclear leukocytes by macrophages. Novel families of locally acting and locally generated mediators derived from omega-3 polyunsaturated fatty acids have also been identified as biosynthetically active components in the resolution phase of inflammation. The new families of chemical mediators are termed 'resolvins' and 'protectins' because individual members of each family are stereospecific in controlling the duration and magnitude of inflammation in animal models. Possible deficiencies in the biosynthesis of lipoxins, resolvins, and protectins, and/or their signal transduction, might underlie some aspects of pathogenesis in chronic inflammatory diseases.

Key Points

  • Resolution is an active process, and endogenous chemical mediators stimulate resolution

  • In exudates, polymorphonuclear leukocytes switch mediator phenotype from generating proinflammatory to proresolving lipid mediators

  • Current therapies that affect resolution include aspirin and glucocorticoids (positive) and COX-2 inhibitors (negative; resolution-toxic)

  • Lipoxins and aspirin-triggered lipoxins are agonists in resolution and therefore protective

  • Novel resolvins and protectins are anti-inflammatory, proresolving, and antifibrotic and are biosynthesized from omega-3 fatty acids

  • Identification of resolution mechanisms and programs can provide new approaches to the treatment of inflammatory disorders with agonists of resolution

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Figure 1: Temporal changes in lipid mediators in the progression of acute inflammation.

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Acknowledgements

We thank M Halm Small for manuscript preparation. This study was supported, in part, by NIH grants GM38765 and P50-DE016191 (CNS). Désirée Lie, University of California, Irvine, CA, is the author of and is solely responsible for the content of the learning objectives, questions and answers of the Medscape-accredited continuing medical education activity associated with this article.

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Authors and Affiliations

  1. Department of Anesthesiology, S Yacoubian is a Research Fellow in the Center for Experimental Therapeutics and Reperfusion Injury, Perioperative and Pain Medicine, Brigham and Women's Hospital, and Harvard Medical School, where CN Serhan is the Director. CN Serhan is also the Simon Gelman Professor of Anesthesia (Biochemistry and Molecular Pharmacology) at Harvard Medical School and Professor of Oral Medicine, Infection and Immunity at Harvard School of Dental Medicine, Boston, MA, USA.,

    Stephanie Yacoubian & Charles N Serhan

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Correspondence to Charles N Serhan.

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The Brigham and Women's Hospital, Boston, MA, USA, is assigned patents on lipoxins and resolvins that are subjects of licensing agreements and consultant arrangements for CN Serhan.

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Yacoubian, S., Serhan, C. New endogenous anti-inflammatory and proresolving lipid mediators: implications for rheumatic diseases. Nat Rev Rheumatol 3, 570–579 (2007). https://doi.org/10.1038/ncprheum0616

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