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The Journal of Immunology, 2005, 174: 4345-4355.
Copyright © 2005 by The American Association of Immunologists

Molecular Circuits of Resolution: Formation and Actions of Resolvins and Protectins1

Gerard L. Bannenberg2, Nan Chiang2, Amiram Ariel, Makoto Arita, Eric Tjonahen, Katherine H. Gotlinger, Song Hong and Charles N. Serhan3

Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA 02115

The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including {Psi}max, the maximal neutrophil numbers that are present during the inflammatory response; Tmax, the time when {Psi}max occurs; and the resolution interval (Ri) from Tmax to T50 when neutrophil numbers reach half {Psi}max. The onset of resolution was at ~12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the Ri. Administration of aspirin-triggered lipoxin A4 analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A4 analog reduced {Psi}max, resolvin E1 decreased both {Psi}max and Tmax, whereas 10,17S-docosatriene reduced {Psi}max, Tmax, and shortened Ri. Also, aspirin-triggered lipoxin A4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20–50% inhibition), whereas resolvin E1 and 10,17S-docosatriene’s inhibitory actions were maximal at 12 h (30–80% inhibition). Moreover, aspirin-triggered lipoxin A4 analog evoked release of the antiphlogistic cytokine TGF-{beta}. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution.




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