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 Apm-. The onset of resolution was at similar to 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 A, analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A, analog reduced Psi(max,) resolvin E1 decreased both Psi(max) and T-max, whereas 10,17S-docosatriene reduced Psi T-max,(max,) and shortened Ri. Also, aspirin-triggered lipoxin A4 analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20-50% inhibition), whereas resolvin El 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 El and 10,17S-docosatriene) to piromote resolution.