The enzymatic oxygenation of polyunsaturated fatty acids by lipoxygenases and cyclo-oxygenases is a resourceful mode of formation of specific autacoids that regulate the extent and pace of the inflammatory response. Arachidonate-derived eicosanoids, such as lipoxin A4, prostaglandin (PG)D2, PGF2&#x3b1;, PGE2, and PGD2-derived cyclopentenones exert specific roles in counter-regulating inflammation and turning on resolution. Recently recognized classes of autacoids derived from long-chain &#x3c9;-3 polyunsaturated fatty acids, the E- and D-series resolvins, protectin D1, and maresin 1, act as specialized mediators to dampen inflammation actively, afford tissue protection, stimulate host defense, and activate resolution. It is held that counter-regulatory lipid mediators and the specific molecular pathways activated by such endogenous agonists may be suitable for pharmacological use in the treatment of inflammatory disease. The anti-inflammatory drug aspirin is a striking example of a drug that is able to act in such a manner, namely through triggering the formation of 15-epi-lipoxin A4 and aspirin-triggered resolvins. Different aspects of the therapeutic applicability of lipid mediators have been addressed here, and indicate that the development of innovative pharmacotherapy based on anti-inflammatory and proresolution lipid mediators presents novel prospects for the treatment of inflammatory disease.

Gerard L. Bannenberg

Therapeutic Applicability of Anti-Inflammatory and Proresolving Polyunsaturated Fatty Acid-Derived Lipid Mediators

Prostanoids are products of cyclooxygenase biosynthetic pathways and constitute a family of lipidic mediators of widely diverse structures and biological actions. Besides their known proinflammatory role, numerous works have revealed the anti-inflammatory effects of various prostanoids and established their role in the resolution of inflammation. Among these, prostaglandins with cyclopentenone structure (cyPG) are electrophilic lipids that may act through various mechanisms, including the activation of nuclear and membrane receptors and, importantly, direct addition to protein cysteine residues and modification of protein function. Due to their ability to influence cysteine modification&#x2013;mediated signaling, cyPG may play a critical role in the interplay between redox and inflammatory signaling pathways. Moreover, cellular redox status modulates cyPG addition to proteins; thus, a reciprocal regulation exists between these two factors. After initial controversy, it is becoming clear that endogenous cyPG are generated at concentrations sufficient to promote inflammatory resolution. As for other prostanoids, cyPG effects are highly dependent on context factors and they may exert pro- or anti-inflammatory actions in a cell type&#x2013;dependent manner, or even biphasic or dual actions in a given cell type or tissue. In light of the growing number of cyPG protein targets identified, cyPG resemble other pleiotropic mediators acting through protein modification. However, their complex structure results in an inter- and intramolecular selectivity of the residues being modified, thus opening the way for structure-activity and drug discovery studies. Detailed characterization of cyPG interactions with cellular proteins will help us to understand their mechanism of action fully and establish their therapeutic potential in inflammation.

Beatriz D&#237;ez-Dacal

Dolores P&#233;rez-Sala

Anti-Inflammatory Prostanoids: Focus on the Interactions between Electrophile Signaling and Resolution of Inflammation

Lipoxins and their 15 epimers, aspirin triggered lipoxins (ATL), are eicosanoids derived from sequential lipoxygenase (LO) metabolism of arachidonic acid. The main routes of lipoxin biosynthesis involve cooperation between 15- and 5-LO, and between 12- and 5-LO. ATL are generated by interactions between 5-LO and aspirin-acetylated cyclooxygenase-2. Cellular models recapitulating these interactions involve leukocytes, platelets, vascular endothelium, and epithelium. To circumvent rapid lipoxin and ATL metabolism and inactivation, stable analogs, bearing potent and long-lasting biological activity, have been synthesized. Some of these analogs displayed therapeutic potential by showing strong anti-inflammatory activity in a number of animal models of disease, including reperfusion injury; arthritis; gastrointestinal, renal, respiratory, and vascular inflammatory disorders; eye damage; periodontitis; and selected infectious diseases. Counter-regulatory signaling by lipoxin A4 and 15-epi-lipoxin A4 is triggered by the activation of a seven-transmembrane domain receptor, termed FPR2/ALX, which is highly expressed in myeloid cells and has been recognized as a main anti-inflammatory receptor.

Mario Romano

Lipoxin and Aspirin-Triggered Lipoxins

The presence of the so-called &#x201C;low-grade&#x201D; inflammatory state is recognized as a critical event in adipose tissue dysfunction in obesity. This chronic &#x201C;low-grade&#x201D; inflammation in white adipose tissue is powerfully augmented through the infiltration of macrophages, which, together with adipocytes, perpetuate a vicious cycle of macrophage recruitment and secretion of free fatty acids and deleterious adipokines that predispose the development of obesity-related comorbidities, such as insulin resistance and nonalcoholic fatty liver disease. In the last decade, many factors have been identified that contribute to mounting uncontrolled inflammation in obese adipose tissue. Among them, bioactive lipid mediators derived from the cyclooxygenase and 5-lipoxygenase pathways, which convert the &#x3C9;-6-polyunsaturated fatty acid (PUFA) arachidonic acid into potent proinflammatory eicosanoids (i.e., prostaglandins [PGs] and leukotrienes), have emerged. Interestingly, the same lipid mediators that initially trigger the inflammatory response also signal the termination of inflammation by stimulating the biosynthesis of anti-inflammatory and proresolving lipid autacoids. This review discusses the current status, characteristics, and progress in this class of &#x201C;stop signals&#x201D;, including the lipoxins, which were the first identified &#x3C9;-6 PUFA&#x2013;derived lipid mediators with potent anti-inflammatory properties; the recently described &#x3C9;-3 PUFA&#x2013;derived lipid mediators resolvins and protectins; and the cyclopentenone PGs of the D series. Special emphasis is given to the participation of these bioactive lipid autacoids in the resolution of adipose tissue inflammation and in preventing the development of obesity-related complications.

Ana Gonz&#225;lez-P&#233;riz

Joan Cl&#224;ria

Resolution of Adipose Tissue Inflammation

Inflammatory diseases of the lung are common, cause significant morbidity, and can be refractory to therapy. Airway responses to injury, noxious stimuli, or microbes lead to leukocyte recruitment for host defense. As leukocytes respond, they interact with lung resident cells and can elaborate specific mediators that are enzymatically generated from polyunsaturated fatty acids via transcellular biosynthesis. These bioactive, lipid-derived, small molecules serve as agonists at specific receptors and are rapidly inactivated in the local environment. This review will focus on the biosynthesis, receptors, cellular responses, and in vivo actions of lipoxins, resolvins, and protectins as exemplary molecular signaling circuits in the airway that are anti-inflammatory and proresolving.

Troy Carlo

Bruce D. Levy

Molecular Circuits of Resolution in Airway Inflammation

Inflammation is the first response of the immune system to infection or injury, but excessive or inappropriate inflammatory responses contribute to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of ω-3 polyunsaturated fatty acids (i.e., eicosapentaenoic acid [EPA] and docosahexaenoic acid [DHA]) indicate that they have beneficial impact on these diseases, although the mechanisms are poorly understood at the molecular level. In this decade, it has been revealed that EPA and DHA are enzymatically converted to bioactive metabolites in the course of acute inflammation and resolution. These metabolites were shown to regulate immune cell functions and to display potent anti-inflammatory actions both in vitro and in vivo. Because of their ability to resolve an acute inflammatory response, they are referred to as proresolving mediators, or resolvins. In this review, we provide an overview of the formation and actions of these lipid mediators.

Hiroyuki Seki

Takaharu Sasaki

Tomomi Ueda

Makoto Arita

Resolvins as Regulators of the Immune System

Inflammation is a common feature of renal pathology. Lipid mediators, such as lipoxins, resolvins, and protectins, can actively promote the resolution of inflammation by inhibiting polymorphonuclear cell infiltration to the site of inflammation, shifting the cytokine milieu from proinflammatory to proresolving and increasing the nonphlogistic phagocytosis of apoptotic cells by macrophages. Here we review the evidence for molecular circuits of resolution in renal disease.

Emma Börgeson

Catherine Godson

Molecular Circuits of Resolution in Renal Disease

Lipid autacoids have well-established key roles in physiology and pathophysiology. Eicosanoids derived from &#x3C9;-6 arachidonic acid (AA) have long been recognized for their roles in cardiovascular and renal functions, and vascular tone, as well as regulating inflammatory and immune functions. It is now appreciated that AA is a substrate for generating lipid mediators with anti-inflammatory and proresolving properties, namely lipoxins (i.e., LXA4), which are an integral component for the successful execution of beneficial and essential acute inflammatory responses. In addition to AA, the &#x3C9;-3 polyunsaturated fatty acids (PUFAs) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) also serve as substrates to generate potent and protective autacoids, such as resolvins and neuroprotectin (i.e., NPD1), respectively. These &#x3C9;-3&#x2013;derived signals may mediate the remarkable protective action of essential dietary &#x3C9;-3 PUFAs. Formation and bioactivity of lipid mediators in the eye are relatively unexplored and of considerable interest, as the eye contains highly specialized tissues, including the transparent avascular and immune-privileged cornea, and the neuro-retina. A rapidly emerging field has identified key biosynthetic enzymes, receptors, and temporally defined endogenous formation of &#x3C9;-3&#x2013; and &#x3C9;-6&#x2013;derived protective lipid circuits in the eye. Protective endogenous roles of LXA4 and NPD1 have been established utilizing lipidomic analysis, knockout mice, and pharmacological, genetic, and dietary manipulation, providing compelling evidence that these intrinsic lipid autacoid circuits play essential roles in restraining inflammation, promoting wound healing, inhibiting pathological angiogenesis, and providing neuroprotection in the delicate visual axis.

Elvira L. Liclican

Karsten Gronert

Molecular Circuits of Resolution in the Eye

Resolution of Acute Inflammation and the Role of Lipid Mediators

About this journal

The Scientific World Journal publishes original research and review articles&nbsp;covering a wide range of subjects in science, technology, and medicine.

Journal profile

Meet the editorial board

The Scientific World Journal maintains an Editorial Board of practicing researchers from around the world, to ensure manuscripts are handled by editors who are experts in the field of study.

Editor spotlight

Submit your proposal

Do you think there is an emerging area of research that really needs to be highlighted? Or an existing research area that has been overlooked or would benefit from deeper investigation? Raise the profile of a research area by leading a Special Issue.

Special Issues

Author guidelines

Editorial board

Databases and indexing

title

The Scientific World Journal publishes original research and review articles covering a wide range of subjects in science, technology, and medicine.

description

https://images.hindawi.com/journals/tswj/tswj.banner.jpg

twitter:card

twitter:description

twitter:site

twitter:title

twitter:url

twitter:image

The Scientific World Journal | Hindawi

The Scientific World Journal

This Issue is now open for submissions.
Papers are published upon acceptance, regardless of the Special Issue publication date.