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

https://doi.org/10.1016/j.bbalip.2010.08.002Get rights and content

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.

Research Highlights

►The resolution of inflammation is actively regulated by specialized pro-resolving mediators (SPM). ►SPM are lipid mediators derived from arachidonic acid and omega-3 poly-unsaturated fatty acids. ►SPM are formed enzymatically during resolution of inflammation. ►SPM include lipoxins, resolvins, protectins, and maresins.

Section snippets

The inflammatory response

The inflammatory response is a local reaction of the vasculature towards a disturbance of tissue homeostasis incurred by damage to tissue structure and infection [1], [2], [3]. Changes in local blood vessel perfusion and permeability permit the directional extravasation of circulating leukocytes that achieve tissue disinfection, and of a range of plasma proteins which play distinct roles in regulating the inflammatory process. Structural alterations of tissue structure that activate the

The “front and back” of acute inflammation

Conserved physiological mechanisms limit the extent and duration of the inflammatory response [4], [24], [25]. These mechanisms can counter-regulate the extent of inflammation (or anti-inflammation), and/or promote the active termination or resolution of inflammation [4], [24]. The former encompasses those mechanisms activated to reduce the rate of granulocyte recruitment to the inflammatory focus and limit their state of activation. The latter comprises the active removal of the granulocytic

Lipoxins and aspirin

Lipoxin A4 (LXA4; (5S,6R,15S-trihydroxy-eicosa-7E,9E,11Z,13E-tetraenoic acid) is a central anti-inflammatory lipid mediator autacoid which plays an important function in determining the extent of granulocyte (neutrophil and eosinophil) accumulation and activation during inflammation. The formation of LXA4 is achieved by transcellular biosynthesis via two sequential oxygenation reactions of arachidonic acid (AA; Fig. 2) catalyzed by lipoxygenases present in interacting cell types, with one of

Specialized pro-resolving lipid mediators (SPM) derived from omega-3 poly-unsaturated fatty acids

A number of enzymatically oxygenated lipid mediators derived from ω-3 poly-unsaturated fatty acids (PUFA), such as EPA and DHA, were recently identified to function as specialized pro-resolution mediators (SPM) that “turn off” the inflammatory response in an active fashion [30]. These mediators, named resolvins, protectins, and maresins, constitute novel families of autacoids with potent anti-inflammatory, tissue-protective, and resolution-stimulating functions. It is important to note that

E-series resolvins: resolvin E1 and resolvin E2

Specific bioactivity was uncovered in the resolving exudates that stopped PMN migration and was 100 times as potent as aspirin in vivo [86]. The active molecule was coined resolvin E1 based on its in vivo production in resolving murine exudates, potent stereoselective actions (demonstrated in vitro and in vivo) and its precursor substrate EPA. Hence, it was important to consider the biosynthetic routes involved in the production of this and related molecules in human cell types. After

D-series resolvins

Given the ability of acetylated COX-2 to accept both AA and EPA as substrates for a single oxygenation reaction to form epimeric fatty acid hydroperoxides, DHA was subsequently tested and recognized as a substrate for acetylated COX-2 as well [92]. In this case oxygen is incorporated at carbon 17, forming a 17R-hydroperoxy group-containing DHA-derived intermediate that when reduced was shown to be 17R-hydroxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid (17R-HpDHA) (Fig. 4). The introduction of

Protectins and maresins

Although transcellular biosynthesis is recognized to be an important requirement for the formation of specific anti-inflammatory and pro-resolution lipid mediators, such as SPM, recent evidence is provided that a single cell type can also form oxygenated lipid mediators with potent counter-regulatory actions. The first pathway involves a 15-lipoxygenase-type I catalyzed formation of the same 17S-hydroperoxy-docosa-4Z,7Z,10Z,13Z,15E,19Z-hexaenoic acid product required for D-series resolvin

Docosapentaenoic acid-derived resolvin-like products

Another ω-3 double-bond-containing PUFA, ω-3 docosapentaenoic acid (DPA; 7Z,10Z,13Z,16Z,19Z-docosapentaenoic acid) has recently been found to be an efficient substrate for oxygenation by 5-, 12-, and 15-lipoxygenases. A number of mono- and dihydroxy fatty acids derived from DPA were identified [129], [130]. Some of these hydroxy products display structural properties akin to pro-resolving protectin D1/NPD1 derived from DHA.

Also the ω-6 double-bond isomer docosapentaenoic acid (ω-6 DPA; 4Z,7Z,10Z

Gauging resolution: quantitative indices

Employing a widely used murine model of self-resolving acute inflammation activated by intraperitoneal administration of zymosan A, we earlier provided a definition of the inflammatory response in a set of quantifiable indices which can be relatively easily measured experimentally (Fig. 1) [89]. A close inspection of these indices for inflammation and resolution indicated that locally administered ATLa2, a stable 15-epi-LXA4 analog, potently reduced inflammation, indicating a significant

Specific molecular events during resolution of the inflammatory response

Recent studies indicate that distinct molecular processes are activated during the resolution phase of inflammation [89]. In addition to the cellular events which characterize resolution, such as leukocyte apoptosis, efferocytosis and egress, a parallel proteomic and mediator lipidomic study of the murine peritonitis model has indicated that distinct molecular events are also activated just prior to and during the resolution interval [89], [90], which can be summarized as follows: i) lipid

Substrate availability: mobilization for resolving exudates

The rapid changes in local blood vessel perfusion and permeability which occur during the early phase of the inflammatory response not only permit directional extravasation of circulating leukocytes and plasma proteins, but also may play an important role in the provision of substrate for SPM biosynthesis. In zymosan-stimulated peritonitis exudate levels of free unacylated ω-3 PUFA AA, EPA, and DHA increase rapidly, reaching maximal levels around 2–4 h (Fig. 1) [89]. Systemically administered

Concluding remarks and further directions

The formation of endogenous autacoids derived from ω-3 PUFA may explain in part the well-known, essential roles of the ω-3 PUFA in human health and disease. More importantly the contribution of novel SPM to the benefits derived from dietary ω-3 FA are beginning to be appreciated with the identification of resolvins as potent autacoids that regulate the resolution phase of the acute inflammatory response [148]. The resolution phase of inflammation has its own regulation involving specific

Conflict of interest statement

The author C.N.S. is an inventor on patents assigned to Brigham and Women's Hospital and Partners HealthCare on the composition of matter, uses, and clinical development of anti-inflammatory and pro-resolving agents. These are licensed for clinical development. C.N.S. retains founder stock in Resolvyx Pharmaceuticals.

Acknowledgements

Work reviewed here in the C.N.S. laboratory was sponsored in part by the National Institutes of Health USA grant nos. GM38765, DE 019938 and DK07448. G. Bannenberg was supported by a Postdoctoral Fellowship from the Arthritis Foundation, and is a Ramón y Cajal fellow at the Centro Nacional de Biotecnología/CSIC, Madrid, Spain. We thank Mary Small for excellent assistance in the preparation of this manuscript and our collaborators and colleagues for their efforts in the original reports reviewed

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