Molecular circuits of resolution: formation and actions of resolvins and protectins.
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; T(max), the time when Psi(max) occurs; and the resolution interval (R(i)) from T(max) to T(50) when neutrophil numbers reach half Psi(max). The onset of resolution was at approximately 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 R(i). Administration of aspirin-triggered lipoxin A(4) analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A(4) analog reduced Psi(max), resolvin E1 decreased both Psi(max) and T(max), whereas 10,17S-docosatriene reduced Psi(max), T(max), and shortened R(i). Also, aspirin-triggered lipoxin A(4) 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 A(4) 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.
Bannenberg
Gerard L
GL
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, USA.
Chiang
Nan
N
Ariel
Amiram
A
Arita
Makoto
M
Tjonahen
Eric
E
Gotlinger
Katherine H
KH
Hong
Song
S
Serhan
Charles N
CN
D000818:Animals; D040502:Calgranulin B / Q000032:analysis; D015777:Eicosanoids / Q000032:analysis; D015118:Eicosapentaenoic Acid / Q000031:analogs & derivatives* / Q000032:analysis*; D005786:Gene Expression Regulation; D006242:Haptoglobins / Q000032:analysis; D007249:Inflammation / Q000473:pathology*; D008055:Lipids / Q000032:analysis; D008297:Male; D013058:Mass Spectrometry; D051379:Mice; D008815:Mice, Inbred Strains; D009504:Neutrophils / Q000378:metabolism / Q000473:pathology*; D011506:Proteins / Q000032:analysis*
D040502:Calgranulin B; D015777:Eicosanoids; D006242:Haptoglobins; D008055:Lipids; D011506:Proteins; D015118:Eicosapentaenoic Acid; C499823:5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid