Anti-inflammatory lipid mediators and insights into the resolution of inflammation

The pro-inflammatory signalling pathways and cellular mechanisms that initiate the inflammatory response have become increasingly well characterized. However, little is known about the mediators and mechanisms that switch off inflammation. Recent data indicate that the resolution of inflammation is an active process controlled by endogenous mediators that suppress pro-inflammatory gene expression and cell trafficking, as well as induce inflammatory-cell apoptosis and phagocytosis, which are crucial determinants of successful resolution. This review focuses on this emerging area of inflammation research and describes the mediators and mechanisms that are currently stealing the headlines.     

调控肺部炎症消退的内源性介质

炎症反应是宿主重要防御机制之一。慢性炎症或过度炎症反应可导致严重的肺部疾病,如哮喘、急性呼吸窘迫综合征等。新近研究表明炎症消退是一个主动过程,炎症的及时消退是防止炎症过强及走向慢性化的关键环节。因此,调控炎症消退的内源性介质成为新的研究热点。促进炎症消退内源性介质的发现不仅为肺部疾病研究提供新视野,也为全新的促炎症消退治疗策略防治肺部疾病提供理论依据。     

Toll-like receptor signaling induces a temporal switch towards a resolving lipid profile in monocyte-derived macrophages

Inflammation is a tightly regulated process. During the past decade it has become clear that the resolution of inflammation is an active process and its dysregulation can contribute to chronic inflammation. Several cells and soluble mediators, including lipid mediators, regulate the course of inflammation and its resolution. It is, however, unclear which signals and cells are involved in initiating the resolution process. Macrophages are tissue resident cells and key players in regulating tissue inflammation through secretion of soluble mediators, including lipids. We hypothesize that persistent inflammatory stimuli can initiate resolution pathways in macrophages.In this study, we detected 21 lipids in LPS-stimulated human monocyte-derived macrophages by liquid chromatography coupled to tandem mass spectrometry. Cyclooxygenase-derived Prostaglandins were observed in the first six hours of stimulation. Interestingly, a switch towards 15-lipoxygenase products, such as the pro-resolving lipid precursors 15-HEPE and 17-HDHA was observed after 24 h. The RNA and protein expression of cyclooxygenase and 15-lipoxygenase were in line with this trend. Treatment with 17-HDHA increased IL-10 production of monocyte-derived macrophages and decreased LTB₄ production by neutrophils, indicating the anti-inflammatory property of this lipid.These data reveal that monocyte-derived macrophages contribute to the resolution of inflammation in time by the production of pro-resolving lipids after an initial inflammatory stimulus.     

Resolvins: natural agonists for resolution of pulmonary inflammation

Inappropriate or excessive pulmonary inflammation can contribute to chronic lung diseases. In health, the resolution of inflammation is an active process that terminates inflammatory responses. The recent identification of endogenous lipid-derived mediators of resolution has provided a window to explore the pathobiology of inflammatory disease and structural templates for the design of novel pro-resolving therapeutics. Resolvins (resolution-phase interaction products) are a family of pro-resolving mediators that are enzymatically generated from essential omega-3 polyunsaturated fatty acids. Two molecular series of resolvins have been characterised, namely E- and D-series resolvins which possess distinct structural, biochemical and pharmacological properties. Acting as agonists at specific receptors (CMKLR1, BLT1, ALX/FPR2 and GPR32), resolvins can signal for potent counter-regulatory effects on leukocyte functions, including preventing uncontrolled neutrophil swarming, decreasing the generation of cytokines, chemokines and reactive oxygen species and promoting clearance of apoptotic neutrophils from inflamed tissues. Hence, resolvins provide mechanisms for cytoprotection of host tissues to the potentially detrimental effects of unresolved inflammation. This review highlights recent experimental findings in resolvin research, and the impact of these stereospecific molecules on the resolution of pulmonary inflammation and tissue catabasis.     

Computational Identification of Mechanistic Factors That Determine the Timing and Intensity of the Inflammatory Response

Timely resolution of inflammation is critical for the restoration of homeostasis in injured or infected tissue. Chronic inflammation is often characterized by a persistent increase in the concentrations of inflammatory cells and molecular mediators, whose distinct amount and timing characteristics offer an opportunity to identify effective therapeutic regulatory targets. Here, we used our recently developed computational model of local inflammation to identify potential targets for molecular interventions and to investigate the effects of individual and combined inhibition of such targets. This was accomplished via the development and application of computational strategies involving the simulation and analysis of thousands of inflammatory scenarios. We found that modulation of macrophage influx and efflux is an effective potential strategy to regulate the amount of inflammatory cells and molecular mediators in both normal and chronic inflammatory scenarios. We identified three molecular mediators − tumor necrosis factor-α (TNF-α), transforming growth factor-β (TGF-β), and the chemokine CXCL8 − as potential molecular targets whose individual or combined inhibition may robustly regulate both the amount and timing properties of the kinetic trajectories for neutrophils and macrophages in chronic inflammation. Modulation of macrophage flux, as well as of the abundance of TNF-α, TGF-β, and CXCL8, may improve the resolution of chronic inflammation.     

A search for endogenous mechanisms of anti-inflammation uncovers novel chemical mediators: missing links to resolution

Multicellular responses to infection, injury, or inflammatory stimuli lead to the formation and release of a wide range of local chemical mediators by the host. The integrated response of the host is essential in health and disease, thus it is important to achieve a more complete understanding of the local cellular and molecular events that govern the formation and actions of local mediators that can serve as endogenous counter-regulatory functions in effector cells of the immune system or endogenous local mediators of resolution. Since these compounds in theory and in experimental models of inflammation appear to control the duration and magnitude of inflammation, knowledge of their elucidation could provide new avenues for appreciating the molecular phenotypes of many inflammatory diseases. The first of these endogenous local counter-regulators recognized were the lipoxins, which are trihydroxytetraene-containing lipid mediators that can be formed during cell–cell interactions via transcellular biosynthesis. Since this circuit of lipoxin formation and action appears to be of physiological relevance for the resolution of inflammation, therapeutic modalities targeted at this system are likely to have fewer unwanted side effects acting as agonists than the inhibitor approach currently used in anti-inflammatory therapies. This chapter provides an overview of the recent knowledge about the biosynthesis and bioactions of the novel anti-inflammatory lipid mediators, resolvins, docosatrienes, and neuroprotectins, and their aspirin-triggered counterparts. These novel families of lipid-derived mediators, which carry anti-inflammatory, pro-resolving, and protective properties, were originally isolated during spontaneous resolution. These new pathways open new opportunities for appreciating the role of neutrophils in the generation of potent protective lipid mediators and protective host signaling.     

Eicosanoids in asthma, allergic inflammation, and host defense

Eicosanoids are diverse mediators of inflammation that derive from a single cell membrane phospholipid-associated precursor, arachidonic acid. This precursor is metabolized to several groups of lipid mediators, including (but not limited to) prostaglandins, leukotrienes, and lipoxins, in a tightly regulated, coordinated, cell- and context-specific manner. Each mediator serves regulatory and homeostatic functions in the onset and resolution of inflammation, immune responses, and tissue repair. The cloning of biosynthetic enzymes and G protein-coupled receptors for each of these mediators, the development of transgenic mice deficient in these molecules, and the availability of selective antagonists have permitted studies that have rapidly expanded our understanding of the scope of biologic functions for these mediators, with potential ramifications for the pathogenesis and treatment of human asthma. This review summarizes these findings and reviews the data from both mouse and human studies pertinent to the pathobiologic role of each mediator.     

Resolvin d1 and aspirin-triggered resolvin d1 promote resolution of allergic airways responses

Asthma is a disease of airway inflammation that in most cases fails to resolve. The resolution of inflammation is an active process governed by specific chemical mediators, including D-series resolvins. In this study, we determined the impact of resolvin D1 (RvD1) and aspirin-triggered RvD1 (AT-RvD1) on the development of allergic airway responses and their resolution. Mice were allergen sensitized, and RvD1, AT-RvD1 (1, 10, or 100 ng), or vehicle was administered at select intervals before or after aerosol allergen challenge. RvD1 markedly decreased airway eosinophilia and mucus metaplasia, in part by decreasing IL-5 and IκBα degradation. For the resolution of established allergic airway responses, AT-RvD1 was even more efficacious than RvD1, leading to a marked decrease in the resolution interval for lung eosinophilia, decrements in select inflammatory peptide and lipid mediators, and more rapid resolution of airway hyperreactivity to methacholine. Relative to RvD1, AT-RvD1 resisted metabolic inactivation by macrophages, and AT-RvD1 significantly enhanced macrophage phagocytosis of IgG-OVA-coated beads in vitro and in vivo, a new proresolving mechanism for the clearance of allergen from the airways. In conclusion, RvD1 and AT-RvD1 can serve as important modulators of allergic airway responses by decreasing eosinophils and proinflammatory mediators and promoting macrophage clearance of allergen. Together, these findings identify D-series resolvins as potential proresolving therapeutic agents for allergic responses.     

Resolvins and protectins: Natural pharmacophores for resolution biology

Dietary ingestion of fish is associated with a reduced risk for many common human illnesses. Fish oils are enriched with n-3 polyunsaturated fatty acids eicosapentaenoic acid and docosahexaenoic acid. Resolvins and protectins are newly discovered mediators that are enzymatically generated from these n-3 fatty acid precursors to orchestrate inflammation resolution. These natural compounds and their mimetics are providing intriguing evidence in model systems and translational research for cellular and molecular mechanisms that are active during catabasis. This review provides information on the biosynthesis and actions of these recently identified chemical mediators with particular reference to resolution of mucosal inflammatory responses.     

Selenium and selenoproteins in prostanoid metabolism and immunity

Abstract

Selenium (Se) is an essential trace element that functions in the form of the 21st amino acid, selenocysteine (Sec) in a defined set of proteins. Se deficiency is associated with pathological conditions in humans and animals, where incorporation of Sec into selenoproteins is reduced along with their expression and catalytic activity. Supplementation of Se-deficient population with Se has shown health benefits suggesting the importance of Se in physiology. An interesting paradigm to explain, in part, the health benefits of Se stems from the observations that selenoprotein-dependent modulation of inflammation and efficient resolution of inflammation relies on mechanisms involving a group of bioactive lipid mediators, prostanoids, which orchestrate a concerted action toward maintenance and restoration of homeostatic immune responses. Such an effect involves the interaction of various immune cells with these lipid mediators where cellular redox gatekeeper functions of selenoproteins further aid in not only dampening inflammation, but also initiating an effective and active resolution process. Here we have summarized the current literature on the multifaceted roles of Se/selenoproteins in the regulation of these bioactive lipid mediators and their immunomodulatory effects.     

Antimicrobial aspects of inflammatory resolution in the mucosa: a role for proresolving mediators

Mucosal surfaces function as selectively permeable barriers between the host and the outside world. Given their close proximity to microbial Ags, mucosal surfaces have evolved sophisticated mechanisms for maintaining homeostasis and preventing excessive acute inflammatory reactions. The role attributed to epithelial cells was historically limited to serving as a selective barrier; in recent years, numerous findings implicate an active role of the epithelium with proresolving mediators in the maintenance of immunological equilibrium. In this brief review, we highlight new evidence that the epithelium actively contributes to coordination and resolution of inflammation, principally through the generation of anti-inflammatory and proresolution lipid mediators. These autacoids, derived from ω-6 and ω-3 polyunsaturated fatty acids, are implicated in the initiation, progression, and resolution of acute inflammation and display specific, epithelial-directed actions focused on mucosal homeostasis. We also summarize present knowledge of mechanisms for resolution via regulation of epithelial-derived antimicrobial peptides in response to proresolving lipid mediators.     

促炎症消退新介质：消退素与保护素

炎症启动（initiation）、发展之后的消退（resolution）是受到体内促消退介质（pro-resolving mediator）调控的主动过程。继发现由花生四烯酸衍生的脂氧素（lipoxin）后,新近又从炎症消退阶段的炎性渗出物中分离出由ω-3多不饱和脂肪酸转化而来的消退素（resolvin）与保护素（protectin）,它们也具有强效的抗炎促消退效应,成为促炎症消退介质的新成员。     

A Novel Anti-Inflammatory and Pro-Resolving Role for Resolvin D1 in Acute Cigarette Smoke-Induced Lung Inflammation

Introduction

Cigarette smoke is a profound pro-inflammatory stimulus that contributes to acute lung injuries and to chronic lung disease including COPD (emphysema and chronic bronchitis). Until recently, it was assumed that resolution of inflammation was a passive process that occurred once the inflammatory stimulus was removed. It is now recognized that resolution of inflammation is a bioactive process, mediated by specialized lipid mediators, and that normal homeostasis is maintained by a balance between pro-inflammatory and pro-resolving pathways. These novel small lipid mediators, including the resolvins, protectins and maresins, are bioactive products mainly derived from dietary omega-3 and omega-6 polyunsaturated fatty acids (PUFA). We hypothesize that resolvin D1 (RvD1) has potent anti-inflammatory and pro-resolving effects in a model of cigarette smoke-induced lung inflammation.

Methods

Primary human lung fibroblasts, small airway epithelial cells and blood monocytes were treated with IL-1β or cigarette smoke extract in combination with RvD1 in vitro, production of pro-inflammatory mediators was measured. Mice were exposed to dilute mainstream cigarette smoke and treated with RvD1 either concurrently with smoke or after smoking cessation. The effects on lung inflammation and lung macrophage populations were assessed.

Results

RvD1 suppressed production of pro-inflammatory mediators by primary human cells in a dose-dependent manner. Treatment of mice with RvD1 concurrently with cigarette smoke exposure significantly reduced neutrophilic lung inflammation and production of pro-inflammatory cytokines, while upregulating the anti-inflammatory cytokine IL-10. RvD1 promoted differentiation of alternatively activated (M2) macrophages and neutrophil efferocytosis. RvD1 also accelerated the resolution of lung inflammation when given after the final smoke exposure.

Conclusions

RvD1 has potent anti-inflammatory and pro-resolving effects in cells and mice exposed to cigarette smoke. Resolvins have strong potential as a novel therapeutic approach to resolve lung injury caused by smoke and pulmonary toxicants.     

Protectin D1 is generated in asthma and dampens airway inflammation and hyperresponsiveness

Protectins are newly identified natural chemical mediators that counter leukocyte activation to promote resolution of inflammation. In this study, we provide the first evidence for protectin D1 (PD1, 10R,17S-dihydroxy-docosa-4Z,7Z,11E,13E,15Z,19Z-hexaenoic acid) formation from docosahexaenoic acid in human asthma in vivo and PD1 counterregulatory actions in allergic airway inflammation. PD1 and 17S-hydroxy-docosahexaenoic acid were present in exhaled breath condensates from healthy subjects. Of interest, levels of PD1 were significantly lower in exhaled breath condensates from subjects with asthma exacerbations. PD1 was also present in extracts of murine lungs from both control animals and those sensitized and aerosol challenged with allergen. When PD1 was administered before aeroallergen challenge, airway eosinophil and T lymphocyte recruitment were decreased, as were airway mucus, levels of specific proinflammatory mediators, including IL-13, cysteinyl leukotrienes, and PGD(2), and airway hyperresponsiveness to inhaled methacholine. Of interest, PD1 treatment after aeroallergen challenge markedly accelerated the resolution of airway inflammation. Together, these findings provide evidence for endogenous PD1 as a pivotal counterregulatory signal in allergic airway inflammation and point to new therapeutic strategies for modulating inflammation in asthmatic lung.     

COX-2 in inflammation and resolution

Aspirin and the other NSAIDs have popularized the notion of inhibiting prostaglandins as a common anti-inflammatory strategy based on the erroneous premise that all eicosanoids are, within the context of inflammation, generally detrimental. However, our fascination with aspirin and the emergence of COX-2 has shown a more affable side to lipid mediators based on our increasing interest in the endogenous control of acute inflammation and in factors that mediate its resolution. Epilipoxins, for instance, are produced from aspirin's acetylation of COX-2 and together with Resolvins and COX-2-derived prostaglandins of the D(2) and J(2) series represent an increasingly important family of immunoregulatory lipid mediators with strong implications for disease control and drug discovery.     

Novel docosatrienes and 17S-resolvins generated from docosahexaenoic acid in murine brain,human blood,and glial cells. Autacoids in anti-inflammation

Docosahexaenoic acid (DHA, C22:6) is highly enriched in brain, synapses, and retina and is a major omega-3 fatty acid. Deficiencies in this essential fatty acid are reportedly associated with neuronal function, cancer, and inflammation. Here, using new lipidomic analyses employing high performance liquid chromatography coupled with a photodiode-array detector and a tandem mass spectrometer, a novel series of endogenous mediators was identified in blood, leukocytes, brain, and glial cells as 17S-hydroxy-containing docosanoids denoted as docosatrienes (the main bioactive member of the series was 10,17S-docosatriene) and 17S series resolvins. These novel mediators were biosynthesized via epoxide-containing intermediates and proved potent (pico- to nanomolar range) regulators of both leukocytes reducing infiltration in vivo and glial cells blocking their cytokine production. These results indicate that DHA is the precursor to potent protective mediators generated via enzymatic oxygenations to novel docosatrienes and 17S series resolvins that each regulate events of interest in inflammation and resolution.     

Taking insult from injury: lipoxins and lipoxin receptor agonists and phagocytosis of apoptotic cells

Phagocytic clearance of apoptotic cells plays a pivotal role in the resolution of inflammation. Recent evidence has shown that such processes can be regulated by endogenous mediators, suggesting that specific mimetics may have therapeutic potential in chronic inflammation and autoimmune disorders. Here we review the mechanisms underlying recognition and engulfment of apoptotic cells and regulation of these processes by lipoxins and lipoxin receptor agonists.