Specialized pro-resolving lipid mediators in the inflammatory response: An update

Abstract

A new genus of specialized pro-resolving mediators (SPM) which include several families of distinct local mediators (lipoxins, resolvins, protectins, and maresins) are actively involved in the clearance and regulation of inflammatory exudates to permit restoration of tissue homeostasis. Classic lipid mediators that are temporally regulated are formed from arachidonic acid, and novel local mediators were uncovered that are biosynthesized from ω-3 poly-unsaturated fatty acids, such as eicosapentaenoic acid, docosapentaenoic acid and docosahexaenoic acid. The biosynthetic pathways for resolvins are constituted by fatty acid lipoxygenases and cyclooxygenase-2 via transcellular interactions established by innate immune effector cells which migrate from the vasculature to inflamed tissue sites. SPM provide local control over the execution of an inflammatory response towards resolution, and include recently recognized actions of SPM such as tissue protection and host defense. The structural families of the SPM do not resemble classic eicosanoids (PG or LT) and are novel structures that function uniquely via pro-resolving cellular and molecular targets. The extravasation of inflammatory cells expressing SPM biosynthetic routes are matched by the temporal provision of essential fatty acids from circulation needed as substrate for the formation of SPM. The present review provides an update and overview of the biosynthetic pathways and actions of SPM, and examines resolution as an integrated component of the inflammatory response and its return to homeostasis via biochemically active resolution mechanisms.

Figure 1

Panel A. The inflammatory response comprises concerted actions by resident parenchymal cells, tissue-resident macrophages and the endothelium. The first steps comprise PMN adhesion to endothelium, diapedesis, chemotaxis towards microbes, and cell activation. The first cells recruited to a disturbed site are PMN, which remove infecting microbes and dead parenchymal cells by phagocytosis. After completion of their function or intrinsic timeline, PMNs undergo apoptosis and are phagocytosed in a non-phlogistic manner by infiltrating monocytes that differentiate into macrophages. Macrophages disappear by tissue egress or apoptosis. Panel B. The inflammatory response can be defined in quantitatively measurable indices based on neutrophil kinetics in the inflammatory focus. Resolution is defined here as the disappearance of the neutrophilic infiltrate. T_max is the time point at which neutrophil numbers are maximal (Ψ_max), T₅₀ is the time point when half of the neutrophils have disappeared. The time interval between T_max and T₅₀ is the resolution interval (Ri), and indicates the duration of the resolution process. Panel C. Appearance of systemic ω-3 PUFA in the inflammatory exudate. Illustrated time courses are depicted graphically based on measurements of the levels of deuterium-labeled EPA and DHA administered systemically in mice 5 minutes prior to initiation of zymosan A-stimulated peritonitis [142]. Panel D. Levels of free arachidonic acid (AA) and ω-3 PUFA in inflammatory exudates during the inflammatory response. Illustrated time courses are depicted graphically based on measurements of cell-free exudate levels made during zymosan A-stimulated murine peritonitis [89]. Panel E. Formation of pro-resolution pathway biomarkers: 17S-hydroxydocosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid (17-HDHA), protectin D1 and 14S-hydroxydocosa-4Z,7Z,10Z,12E,16Z,19Z-hexaenoic acid (14-HDHA) during the acute inflammatory response. In this model of inflammation the formation of protectin D1 was found to increase during the resolution interval. The time course is depicted graphically based on measurements of cell-free exudate levels made during zymosan A-stimulated murine peritonitis [89].

Figure 2

Biosynthesis of lipoxins and aspirin-triggered lipoxins.

Figure 3

Biosynthesis of E-series resolvins: RvE1 and RvE2.

Figure 4

Biosynthesis of D-series resolvins. Inset, one example of an aspirin-triggered D-series resolvin, AT-RvD1 (7S,8,17R-trihydroxy-docosa-4Z,9E,11E,13Z,15E,19Z-hexaenoic acid), displaying predominately the R-stereospecificity at the carbon-17 alcohol group.

Figure 5

A. Biosynthesis of protectins: protectin D1 (10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), the mono-hydroxylated product 17S-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid, and the double oxygenation product 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid, an isomer of NPD1/PD1 (see text for details). B. Formation of maresins: maresin 1 (7,14S-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid); the geometry of the double bonds depicted is tentative and in progress (see text for details). Also, an isomer 7S,14S-dihydroxydocosa-4Z,8E,10Z,12E,16Z,19Z-hexaenoic acid, a novel double dioxygenation product.

Figure 5

A. Biosynthesis of protectins: protectin D1 (10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid), the mono-hydroxylated product 17S-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid, and the double oxygenation product 10S,17S-dihydroxy-docosa-4Z,7Z,11E,13Z,15E,19Z-hexaenoic acid, an isomer of NPD1/PD1 (see text for details). B. Formation of maresins: maresin 1 (7,14S-dihydroxydocosa-4Z,8,10,12,16Z,19Z-hexaenoic acid); the geometry of the double bonds depicted is tentative and in progress (see text for details). Also, an isomer 7S,14S-dihydroxydocosa-4Z,8E,10Z,12E,16Z,19Z-hexaenoic acid, a novel double dioxygenation product.