Potential Clinical Applications of Pro-Resolving Lipids Mediators from Docosahexaenoic Acid (original) (raw)
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Acute inflammatory response is composed of two distinct steps: initiation and resolution. Actually, it is now well accepted that inflammation is a self-limited process which encompasses in its terminal step the repair of injured tissues and the return to homeostasis. The omega-3 fatty acids EicosaPentaenoic Acid (EPA) and DocosaHexaenoic Acid (DHA) have long been held to display anti-inflammatory and pro-resolution properties. The omega-3 fatty acids represent the substrates for the synthesis of several molecules, such as resolvins, protectins and maresins collectively termed as Specialized Pro-resolving Mediators (SPMs). The action mechanism of SPMs generally bases on binding to specific receptors and are basically finalized to promote both the interruption of inflammatory response and the promotion of tissue repair. Several studies demonstrate the action of resolvins in different districts of the body, including blood vessels, airway, skin, kidneys, eyes and nervous system. Moreover, the benefic role of SPMs has been also demonstrated in metabolic diseases and infective processes. Thus, there is a growing interest towards the role of n-3 derivatives in different pathological conditions and further studies could allow their use as new and more effective therapeutic tools.
Bioorganic & Medicinal Chemistry Letters, 2017
Several novel oxygenated polyunsaturated lipid mediators biosynthesized from n-3 docosapentaenoic acid were recently isolated from murine inflammatory exudates and human primary cells. These compounds belong to a distinct family of specialized pro-resolving lipid mediators, and display potent in vivo anti-inflammatory and pro-resolution effects. The endogenously formed specialized pro-resolving mediators have attracted a great interest as lead compounds in drug discovery programs towards the development of new classes of drugs that dampen inflammation without interfering with the immune response. Detailed information on the chemical structures, cellular functions and distinct biosynthetic pathways of specialized pro-resolving lipid mediators is a central aspect of these efforts. Herein, the isolation, structural elucidation, biosynthetic pathways, total synthesis and bioactions of the n-3 docosapentaenoic acid derived mediators PD1 n-3 DPA and MaR1 n-3 DPA are discussed. In addition, a brief discussion of a novel family of mediators derived from n-3 docosapentaenoic acid, termed 13-series resolvins is included.
Resolvins and protectins: novel lipid mediators in anti-inflammation and resolution
Food & Nutrition Research, 2006
A well-integrated inflammatory response and its natural resolution are essential to homeostasis. Hence, it is important to achieve a complete understanding of the molecular events that govern termination of acute inflammation. Recent studies uncovered endogenous pathways in inflammatory exudates taken from the resolution phase that actively generate new families of locally acting mediators from the essential fatty acids eicosapentaenoic acid and docosahexaenoic acid. These new chemical families were coined resolvins and protectins because in animals specific members of these families control the duration and magnitude of inflammation. Hence, mapping of these resolution circuits, mediators and their target signaling pathways of these potent agonists of resolution has provided new avenues for appreciating the molecular basis of many inflammatory diseases. This overview covers recent advances on the biosynthesis and actions of these novel anti-inflammatory lipid mediators, with a focus on the stereochemical basis of the potent actions of resolvin E1 and protectin D1. These previously unappreciated families of lipid-derived mediators were originally isolated from experimental murine models of acute inflammation captured during natural self-limited resolution. Since they have proven anti-inflammatory, proresolving, and protective properties in experimental models of disease, it follows that potential defective resolution mechanism(s) may underlie the current appreciation of inflammatory disease phenotype(s).
Anti-Inflammatory and Proresolving Lipid Mediators
Annual Review of Pathology: Mechanisms of Disease, 2008
The popular view that all lipid mediators are pro-inflammatory arises largely from the finding that non-steroidal anti-inflammatory drugs block the biosynthesis of prostaglandins. The resolution of inflammation was widely held to be a passive event until recently, with the characterization of novel biochemical pathways and lipid-derived mediators that are actively turned on in resolution possessing potent anti-inflammatory and pro-resolving actions. A lipid mediator informatics approach was employed to systematically identify new families of endogenous local-acting mediators from omega-3-polyunsaturated fatty acids (eicosapentaenoic acid and docosahexaenoic acid) in resolving exudates in addition to the lipoxins and aspirin-triggered lipoxins generated from arachidonic acid. These new chemical mediator families were coined resolvins and protectins, given their potent bioactions. In this annual review, we present recent advances on the biosynthesis and stereospecific actions of these new pro-resolving mediators, which have also proven to be organ protective and anti-fibrotic.
Specialized pro-resolving lipid mediators in the inflammatory response: An update
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids, 2010
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.
Novel Lipid Mediators and Resolution Mechanisms in Acute Inflammation: To Resolve or Not?
The American Journal of Pathology, 2010
Because inflammation is appreciated as a unifying basis of many widely occurring diseases, the mechanisms involved in its natural resolution are of considerable interest. Using contained, self-limited inflammatory exudates and a systems approach, novel lipid-derived mediators and pathways were uncovered in the resolution of inflammatory exudates. These new families of local mediators control both the duration and magnitude of acute inflammation as well as the return of the site to homeostasis in the process of catabasis. This new genus of specialized proresolving mediators (SPM) includes essential fatty acid-derived lipoxins, resolvins, protectins, and, most recently, maresins. These families were named based on their unique structures and potent stereoselective actions. The temporally initiated biosynthesis of SPM and their direct impact on leukocyte trafficking and macrophage-directed clearance mechanisms provide clear evidence that resolution is an active, programmed response at the tissue level. Moreover, SPM that possess anti-inflammatory (ie, limiting PMN infiltration) and proresolving (enhance macrophage uptake and clearance of apoptotic PMN and microbial particles) actions as well as stimulating mucosal antimicrobial responses demonstrate that antiinflammation and proresolution are different responses of the host and novel defining properties of these molecules. The mapping of new resolution circuits has opened the possibility for understanding mechanisms that lead from acute to chronic inflammation , or to the resolution thereof , as well as to potential , resolution-based immunopharmacological therapies.
Journal of Experimental Medicine, 2002
Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17 R -hydroxy-containing di-and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17 R -hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17 R -HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA-derived 17 R -hydroxy-DHA into two sets of novel diand trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC 50 ف 50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40-80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17 R -hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.
Lipoxins and new lipid mediators in the resolution of inflammation
Current Opinion in Pharmacology, 2006
Lipoxins and aspirin-triggered lipoxins are lipid mediators generated from arachidonic acid that act to reduce inflammation and promote resolution. In addition, two new families of lipid mediators were uncovered, namely resolvins (resolution phase interaction products) and protectins, which derive from omega-3 polyunsaturated fatty acid. They possess potent anti-inflammatory, neuroprotective and pro-resolving properties. Eicosapentaenoic acid-derived mediators are denoted resolvins of the E series, and those biosynthesized from docosahexaenoic acid are resolvins of the D series (RvDs) and protectins. Aspirin impinges on these systems, triggering formation of the epimeric 17R-series RvDs-denoted as 'aspirin-triggered-RvDs'-which possess bioactivity in vivo equivalent to that evoked by their 17S-series counterparts (i.e. RvDs). These bioactive molecules open new avenues and approaches to therapeutic interventions via accelerated resolution of inflammation.