Lipoxin Mimetics and the Resolution of Inflammation.

Inflammation and its timely resolution are critical to ensure effective host defense and appropriate tissue repair after injury and or infection. Chronic, unresolved inflammation typifies many prevalent pathologies. The key mediators that initiate and drive the inflammatory response are well defined and targeted by conventional anti-inflammatory therapeutics. More recently, there is a growing appreciation that specific mediators, including arachidonate-derived lipoxins, are generated in self-limiting inflammatory responses to promote the resolution of inflammation and endogenous repair mechanisms without compromising host defense. We discuss the proresolving biological actions of lipoxins and recent efforts to harness their therapeutic potential through the development of novel, potent lipoxin mimetics generated via efficient, modular stereoselective synthetic pathways. We consider the evidence that lipoxin mimetics may have applications in limiting inflammation and reversing fibrosis and the underlying mechanisms.

Specialized Proresolving Mediators in Innate and Adaptive Immune Responses in Airway Diseases.

Airborne pathogens and environmental stimuli evoke immune responses in the lung. It is critical to health that these responses be controlled to prevent tissue damage and the compromise of organ function. Resolution of inflammation is a dynamic process that is coordinated by biochemical and cellular mechanisms. Recently, specialized proresolving mediators (SPMs) have been identified in resolution exudates. These molecules orchestrate anti-inflammatory and proresolving actions that are cell type specific. In this review, we highlight SPM biosynthesis, the influence of SPMs on the innate and adaptive immune responses in the lung, as well as recent insights from SPMs on inflammatory disease pathophysiology. Uncovering these mediators and cellular mechanisms for resolution is providing new windows into physiology and disease pathogenesis.

15-epi-lipoxin A5 promotes neutrophil exit from exudates for clearance by splenic macrophages.

Specialized proresolving mediators (SPMs) promote local macrophage efferocytosis but excess leukocytes early in inflammation require additional leukocyte clearance mechanism for resolution. Here, neutrophil clearance mechanisms from localized acute inflammation were investigated in mouse dorsal air pouches. 15-HEPE (15-hydroxy-5Z,8Z,11Z,13E,17Z-eicosapentaenoic acid) levels were increased in the exudates. Activated human neutrophils converted 15-HEPE to lipoxin A5 (5S,6R,15S-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), 15-epi-lipoxin A5 (5S,6R,15R-trihydroxy-7E,9E,11Z,13E,17Z-eicosapentaenoic acid), and resolvin E4 (RvE4; 5S,15S-dihydroxy-6E,8Z,11Z,13E,17Z-eicosapentaenoic acid). Exogenous 15-epi-lipoxin A5, 15-epi-lipoxin A4 and a structural lipoxin mimetic significantly decreased exudate neutrophils and increased local tissue macrophage efferocytosis, with comparison to naproxen. 15-epi-lipoxin A5 also cleared exudate neutrophils faster than the apparent local capacity for stimulated macrophage efferocytosis, so the fate of exudate neutrophils was tracked with CD45.1 variant neutrophils. 15-epi-lipoxin A5 augmented the exit of adoptively transferred neutrophils from the pouch exudate to the spleen, and significantly increased splenic SIRPa+ and MARCO+ macrophage efferocytosis. Together, these findings demonstrate new systemic resolution mechanisms for 15-epi-lipoxin A5 and RvE4 in localized tissue inflammation, which distally engage the spleen to activate macrophage efferocytosis for the clearance of tissue exudate neutrophils.

Lipoxins A4 and B4 inhibit glial cell activation via CXCR3 signaling in acute retinal neuroinflammation.

Lipoxins are small lipids that are potent endogenous mediators of systemic inflammation resolution in a variety of diseases. We previously reported that Lipoxins A4 and B4 (LXA4 and LXB4) have protective activities against neurodegenerative injury. Yet, lipoxin activities and downstream signaling in neuroinflammatory processes are not well understood. Here, we utilized a model of posterior uveitis induced by lipopolysaccharide endotoxin (LPS), which results in rapid retinal neuroinflammation primarily characterized by activation of resident macroglia (astrocytes and Müller glia), and microglia. Using this model, we observed that each lipoxin reduces acute inner retinal inflammation by affecting endogenous glial responses in a cascading sequence beginning with astrocytes and then microglia, depending on the timing of exposure; prophylactic or therapeutic. Subsequent analyses of retinal cytokines and chemokines revealed inhibition of both CXCL9 (MIG) and CXCL10 (IP10) by each lipoxin, compared to controls, following LPS injection. CXCL9 and CXCL10 are common ligands for the CXCR3 chemokine receptor, which is prominently expressed in inner retinal astrocytes and ganglion cells. We found that CXCR3 inhibition reduces LPS-induced neuroinflammation, while CXCR3 agonism alone induces astrocyte reactivity. Together, these data uncover a novel lipoxin-CXCR3 pathway to promote distinct anti-inflammatory and proresolution cascades in endogenous retinal glia.

A signaling network map of Lipoxin (LXA4): an anti-inflammatory molecule.

Lipoxins (LXs) are a class of endogenous bioactive lipid mediators that are involved in the regulation of inflammation. They exert immunomodulatory effects by regulating the behaviour of various immune cells, including neutrophils, macrophages, and T and B cells, by promoting the clearance of apoptotic neutrophils. This helps to dampen inflammation and promote tissue repair. LXs regulate the expression of many inflammatory genes by modulating the levels of transcription factors, such as nuclear factor κB (NF-κB), activator protein-1 (AP-1), nerve growth factor-regulated factor 1A binding protein 1 (NGF), and peroxisome proliferator activated receptor γ (PPAR-γ), which are elevated in various diseases, such as respiratory tract diseases, renal diseases, cancer, neurodegenerative diseases, and viral infections. Lipoxin-mediated signaling is involved in chronic inflammation, cancer, diabetes-associated kidney disease, lung injury, liver injury, endometriosis, respiratory tract diseases, neurodegenerative diseases, chronic cerebral hypoperfusion, and retinal degeneration. In this study, we systematically investigated the intricate network of lipoxin signaling by analyzing the relevant literature. The resulting map comprised 467 molecules categorized as activation/inhibition, enzyme catalysis, gene and protein expression, molecular associations, and translocation events. This map serves as a valuable resource for understanding the complexity of lipoxin signaling and its impact on various cellular functions.

Double peroxidase and histone acetyltransferase AgTip60 maintain innate immune memory in primed mosquitoes.

Immune priming in Anopheles gambiae is mediated by the systemic release of a hemocyte differentiation factor (HDF), a complex of lipoxin A4 bound to Evokin, a lipid carrier. HDF increases the proportion of circulating granulocytes and enhances mosquito cellular immunity. Here, we show that Evokin is present in hemocytes and fat-body cells, and messenger RNA (mRNA) expression increases significantly after immune priming. The double peroxidase (DBLOX) enzyme, present in insects but not in vertebrates, is essential for HDF synthesis. DBLOX is highly expressed in oenocytes in the fat-body tissue, and these cells increase in number in primed mosquitoes. We provide direct evidence that the histone acetyltransferase AgTip60 (AGAP001539) is also essential for a sustained increase in oenocyte numbers, HDF synthesis, and immune priming. We propose that oenocytes may function as a population of cells that are reprogrammed, and orchestrate and maintain a broad, systemic, and long-lasting state of enhanced immune surveillance in primed mosquitoes.

Advances in the Chemistry and Biology of Specialised Pro-Resolving Mediators (SPMs).

This review article assembles key recent advances in the synthetic chemistry and biology of specialised pro-resolving mediators (SPMs). The major medicinal chemistry developments in the design, synthesis and biological evaluation of synthetic SPM analogues of lipoxins and resolvins have been discussed. These include variations in the top and bottom chains, as well as changes to the triene core, of lipoxins, all changes intended to enhance the metabolic stability whilst retaining or improving biological activity. Similar chemical modifications of resolvins are also discussed. The biological evaluation of these synthetic SPMs is also described in some detail. Original investigations into the biological activity of endogenous SPMs led to the pairing of these ligands with the FPR2/LX receptor, and these results have been challenged in more recent work, leading to conflicting results and views, which are again discussed.

Lipoxins modulate neutrophil oxidative burst, integrin expression and lymphatic transmigration differentially in human health and atherosclerosis.

Dysregulated chronic inflammation plays a crucial role in the pathophysiology of atherosclerosis and may be a result of impaired resolution. Thus, restoring levels of specialized pro-resolving mediators (SPMs) to promote the resolution of inflammation has been proposed as a therapeutic strategy for patients with atherosclerosis, in addition to standard clinical care. Herein, we evaluated the effects of the SPM lipids, lipoxin A4 (LXA4 ) and lipoxin B4 (LXB4 ), on neutrophils isolated from patients with atherosclerosis compared with healthy controls. Patients displayed altered endogenous SPM production, and we demonstrated that lipoxin treatment in whole blood from atherosclerosis patients attenuates neutrophil oxidative burst, a key contributor to atherosclerotic development. We found the opposite effect in neutrophils from healthy controls, indicating a potential mechanism whereby lipoxins aid the endogenous neutrophil function in health but reduce its excessive activation in disease. We also demonstrated that lipoxins attenuated upregulation of the high-affinity conformation of the CD11b/CD18 integrin, which plays a central role in clot activation and atherosclerosis. Finally, LXB4 enhanced lymphatic transmigration of human neutrophils isolated from patients with atherosclerosis. This finding is noteworthy, as impaired lymphatic function is now recognized as an important contributor to atherosclerosis. Although both lipoxins modulated neutrophil function, LXB4 displayed more potent effects than LXA4 in humans. This study highlights the therapeutic potential of lipoxins in atherosclerotic disease and demonstrates that the effect of these SPMs may be specifically tailored to the need of the individual.

Proresolving lipid mediators and mechanisms in the resolution of acute inflammation.

Inflammatory responses, like all biological cascades, are shaped by a delicate balance between positive and negative feedback loops. It is now clear that in addition to positive and negative checkpoints, the inflammatory cascade rather unexpectedly boasts an additional checkpoint, a family of chemicals that actively promote resolution and tissue repair without compromising host defense. Indeed, the resolution phase of inflammation is just as actively orchestrated and carefully choreographed as its induction and inhibition. In this review, we explore the immunological consequences of omega-3-derived specialized proresolving mediators (SPMs) and discuss their place within what is currently understood of the role of the arachidonic acid-derived prostaglandins, lipoxins, and their natural C15-epimers. We propose that treatment of inflammation should not be restricted to the use of inhibitors of the acute cascade (antagonism) but broadened to take account of the enormous therapeutic potential of inducers (agonists) of the resolution phase of inflammation.

Lipoxin-mediated signaling: ALX/FPR2 interaction and beyond.

In the aftermath of tissue injury or infection, an efficient resolution mechanism is crucial to allow tissue healing and preserve appropriate organ functioning. Pro-resolving bioactive lipids prevent uncontrolled inflammation and its consequences. Among these mediators, lipoxins were the first described and their pro-resolving actions have been mainly described in immune cells. They exert their actions mostly through formyl-peptide receptor 2 (ALX/FPR2 receptor), a G-protein-coupled receptor whose biological function is tremendously complex, primarily due to its capacity to mediate variable cellular responses. Moreover, lipoxins can also interact with alternative receptors like the cytoplasmic aryl hydrocarbon receptor, the cysteinyl-leukotrienes receptors or GPR32, triggering different intracellular signaling pathways. The available information about this complex response mediated by lipoxins is addressed in this review, going over the different mechanisms used by these molecules to stop the inflammatory reaction and avoid the development of dysregulated and chronic pathologies.

Formation of lipoxins and resolvins in human leukocytes.

Specialized pro-resolving lipid mediators (SPMs) such as lipoxins or resolvins are formed by the consecutive action of 5-lipoxygenase (5-LO, ALOX5) and different types of arachidonic acid 12- or 15-lipoxygenases using arachidonic acid, eicosapentaenoic acid or docosahexaenoic acid as substrate. Lipoxins are trihydroxylated oxylipins which are formed from arachidonic and eicosapentaenoic acid. The latter can also be converted to di- and trihydroxylated resolvins of the E series, whereas docosahexaenoic acid is the substrate for the formation of di- and trihydroxylated resolvins of the D series. Here, we summarize the formation of lipoxins and resolvins in leukocytes. From the data published so far, it becomes evident that FLAP is required for the biosynthesis of most of the lipoxins and resolvins. Even in the presence of FLAP, formation of the trihydroxylated SPMs (lipoxins, RvD1-RvD4, RvE1) in leukocytes is very low or undetectable which is obviously due to the extremely low epoxide formation by 5-LO from oxylipins such as 15-H(p)ETE, 18-H(p)EPE or 17-H(p)DHA. As a result, only the dihydroxylated oxylipins (5 S,15S-diHETE, 5 S,15S-diHEPE) and resolvins (RvD5, RvE2, RvE4) can be consistently detected using leukocytes as SPM source. However, the reported levels of these dihydroxylated lipid mediators are still much lower than those of the typical pro-inflammatory mediators including the monohydroxylated fatty acid derivatives (e.g. 5-HETE), leukotrienes or cyclooxygenase-derived prostaglandins. Since 5-LO expression is mainly restricted to leukocytes these cells are considered as the main source of SPMs. The low formation of trihydroxylated SPMs in leukocytes, the fact that they are hardly detected in biological samples as well as the lack of functional signaling by their receptors make it highly questionable that trihydroxylated SPMs play a role as endogenous mediators in the resolution of inflammation.

A Stereocontrolled Total Synthesis of Lipoxin B4 and its Biological Activity as a Pro-Resolving Lipid Mediator of Neuroinflammation.

Two stereocontrolled, efficient, and modular syntheses of eicosanoid lipoxin B4 (LXB4 ) are reported. One features a stereoselective reduction followed by an asymmetric epoxidation sequence to set the vicinal diol stereocentres. The dienyne was installed via a one-pot Wittig olefination and base-mediated epoxide ring opening cascade. The other approach installed the diol through an asymmetric dihydroxylation reaction followed by a Horner-Wadsworth-Emmons olefination to afford the common dienyne intermediate. Finally, a Sonogashira coupling and an alkyne hydrosilylation/proto-desilylation protocol furnished LXB4 in 25 % overall yield in just 10 steps. For the first time, LXB4 has been fully characterized spectroscopically with its structure confirmed as previously reported. We have demonstrated that the synthesized LXB4 showed similar biological activity to commercial sources in a cellular neuroprotection model. This synthetic route can be employed to synthesize large quantities of LXB4 , enable synthesis of new analogs, and chemical probes for receptor and pathway characterization.

High levels of eicosanoids and docosanoids in the lungs of intubated COVID-19 patients.

Severe acute respiratory syndrome coronavirus 2 is responsible for coronavirus disease 2019 (COVID-19). While COVID-19 is often benign, a subset of patients develops severe multilobar pneumonia that can progress to an acute respiratory distress syndrome. There is no cure for severe COVID-19 and few treatments significantly improved clinical outcome. Dexamethasone and possibly aspirin, which directly/indirectly target the biosynthesis/effects of numerous lipid mediators are among those options. Our objective was to define if severe COVID-19 patients were characterized by increased bioactive lipids modulating lung inflammation. A targeted lipidomic analysis of bronchoalveolar lavages (BALs) by tandem mass spectrometry was done on 25 healthy controls and 33 COVID-19 patients requiring mechanical ventilation. BALs from severe COVID-19 patients were characterized by increased fatty acids and inflammatory lipid mediators. There was a predominance of thromboxane and prostaglandins. Leukotrienes were also increased, notably LTB4 , LTE4 , and eoxin E4 . Monohydroxylated 15-lipoxygenase metabolites derived from linoleate, arachidonate, eicosapentaenoate, and docosahexaenoate were also increased. Finally yet importantly, specialized pro-resolving mediators, notably lipoxin A4 and the D-series resolvins, were also increased, underscoring that the lipid mediator storm occurring in severe COVID-19 involves pro- and anti-inflammatory lipids. Our data unmask the lipid mediator storm occurring in the lungs of patients afflicted with severe COVID-19. We discuss which clinically available drugs could be helpful at modulating the lipidome we observed in the hope of minimizing the deleterious effects of pro-inflammatory lipids and enhancing the effects of anti-inflammatory and/or pro-resolving lipid mediators.

Pro-resolving lipid mediators: Agents of anti-ageing?

Inflammation is an essential response to injury and its timely and adequate resolution permits tissue repair and avoidance of chronic inflammation. Ageing is associated with increased inflammation, sub-optimal resolution and these act as drivers for a number of ageing-associated pathologies. We describe the role played by specialised proresolving lipid mediators (SPMs) in the resolution of inflammation and how insufficient levels of these mediators, or compromised responsiveness may play a role in the pathogenesis of many ageing-associated pathologies, e.g. Alzheimer's Disease, atherosclerosis, obesity, diabetes and kidney disease. Detailed examination of the resolution phase of inflammation highlights the potential to harness these lipid mediators and or mimetics of their bioactions, in particular, their synthetic analogues to promote effective resolution of inflammation, without compromising the host immune system.

Aspirin-triggered proresolving mediators stimulate resolution in cancer.

Inflammation in the tumor microenvironment is a strong promoter of tumor growth. Substantial epidemiologic evidence suggests that aspirin, which suppresses inflammation, reduces the risk of cancer. The mechanism by which aspirin inhibits cancer has remained unclear, and toxicity has limited its clinical use. Aspirin not only blocks the biosynthesis of prostaglandins, but also stimulates the endogenous production of anti-inflammatory and proresolving mediators termed aspirin-triggered specialized proresolving mediators (AT-SPMs), such as aspirin-triggered resolvins (AT-RvDs) and lipoxins (AT-LXs). Using genetic and pharmacologic manipulation of a proresolving receptor, we demonstrate that AT-RvDs mediate the antitumor activity of aspirin. Moreover, treatment of mice with AT-RvDs (e.g., AT-RvD1 and AT-RvD3) or AT-LXA4 inhibited primary tumor growth by enhancing macrophage phagocytosis of tumor cell debris and counter-regulating macrophage-secreted proinflammatory cytokines, including migration inhibitory factor, plasminogen activator inhibitor-1, and C-C motif chemokine ligand 2/monocyte chemoattractant protein 1. Thus, the pro-resolution activity of AT-resolvins and AT-lipoxins may explain some of aspirin's broad anticancer activity. These AT-SPMs are active at considerably lower concentrations than aspirin, and thus may provide a nontoxic approach to harnessing aspirin's anticancer activity.

Lipoxin A4 regulates M1/M2 macrophage polarization via FPR2-IRF pathway.

Lipoxin A4 (LXA4) has been shown to have anti-inflammatory activity, but its underlying molecular mechanisms are not clear. Herein, we investigated the potential role of LXA4 in macrophage polarization and elucidated its possible molecular mechanism. The RAW264.7 macrophage cell line was pretreated with LXA4 with or without lipopolysaccharides (LPSs) and interleukin-4 (IL-4). In cultured macrophages, LXA4 inhibited LPS-induced inflammatory polarization, thereby decreasing the release of proinflammatory cell factors (IL-1ß, IL-6, TNF-α) and increasing the release of anti-inflammatory cytokines (IL-4 and IL-10). Notably, the inhibitory effect of LXA4 on inflammatory macrophage polarization was related to the downregulation of p-NF-κB p65 and IRF5 activity, which reduced the LPS-induced phenotypic and functional polarization of M1 macrophages via the FPR2/IRF5 signaling pathway. Moreover, LXA4 also induced the IL-4-induced polarization of M2 macrophages by promoting the FPR2/IRF4 signaling pathway. Therefore, LXA4 regulates M1/M2 polarization of macrophages via the FPR2-IRF pathway.

Potential role of lipoxin in the management of COVID-19: a narrative review.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2) infection leads to the development of coronavirus disease 2019 (COVID-19), which causes endothelial dysfunction (ED), oxidative stress (OS), and inflammatory disorders. These changes cause hypoxia and cytokine storm with the development of cardio-pulmonary complications. Bioactive lipids and other polyunsaturated fatty acids participate in a vital role in the SARS-CoV-2 infection process. One of these mediators is the anti-inflammatory compound, lipoxin (LX). LXs are produced from arachidonic acid (AA) by collaboration between 5-lipoxygenase (5-LO) and 12-15 LO during cell interactions. Thus, our goal was to review the probable role of LXs in COVID-19 regarding the effects of LXs on the inflammatory signaling pathways that are linked with COVID-19 pathogenesis and complications.

Concurrent Control of the Kaposi's Sarcoma-Associated Herpesvirus Life Cycle through Chromatin Modulation and Host Hedgehog Signaling: a New Prospect for the Therapeutic Potential of Lipoxin A4.

Lipoxin A4 (LXA4) is an endogenous lipid mediator with compelling anti-inflammatory and proresolution properties. Studies done to assess the role of arachidonic acid pathways of the host in Kaposi's sarcoma-associated herpesvirus (KSHV) biology helped discover that KSHV infection hijacks the proinflammatory cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LO) pathways and concurrently reduces anti-inflammatory LXA4 secretion to maintain KSHV latency in infected cells. Treatment of KSHV-infected cells with LXA4 minimizes the activation of inflammatory and proliferative signaling pathways, including the NF-κB, AKT, and extracellular signal-regulated kinase 1/2 (ERK1/2) pathways, but the exact mechanism of action of LXA4 remains unexplored. Here, using mass spectrometry analysis, we identified components from the minichromosome maintenance (MCM) protein and chromatin-remodeling complex SMARCB1 and SMARCC2 to be LXA4-interacting host proteins in KSHV-infected cells. We identified a higher level of nuclear aryl hydrocarbon receptor (AhR) in LXA4-treated KSHV-infected cells than in untreated KSHV-infected cells, which probably facilitates the affinity interaction of the nucleosome complex protein with LXA4. We demonstrate that SMARCB1 regulates both replication and transcription activator (RTA) activity and host hedgehog (hh) signaling in LXA4-treated KSHV-infected cells. Host hedgehog signaling was modulated in an AMP-activated protein kinase (AMPK)-mammalian target of rapamycin (mTOR)-S6 kinase-dependent manner in LXA4-treated KSHV-infected cells. Since anti-inflammatory drugs are beneficial as adjuvants to conventional and immune-based therapies, we evaluated the potential of LXA4 treatment in regulating programmed death-ligand 1 (PD-L1) on KSHV-carrying tumor cells. Overall, our study identified LXA4-interacting host factors in KSHV-infected cells, which could help provide an understanding of the mode of action of LXA4 and its therapeutic potential against KSHV.IMPORTANCE The latent-to-lytic switch in KSHV infection is one of the critical events regulated by the major replication and transcription activator KSHV protein called RTA. Chromatin modification of the viral genome determines the phase of the viral life cycle in the host. Here, we report that LXA4 interacts with a host chromatin modulator, especially SMARCB1, which upregulates the KSHV ORF50 promoter. SMARCB1 has also been recognized to be a tumor suppressor protein which controls many tumorigenic events associated with the hedgehog (hh) signaling pathway. We also observed that LXA4 treatment reduces PD-L1 expression and that PD-L1 expression is an important immune evasion strategy used by KSHV for its survival and maintenance in the host. Our study underscores the role of LXA4 in KSHV biology and emphasizes that KSHV is strategic in downregulating LXA4 secretion in the host to establish latency. This study also uncovers the therapeutic potential of LXA4 and its targetable receptor, AhR, in KSHV's pathogenesis.

Mycobacterium tuberculosis evades macrophage defenses by inhibiting plasma membrane repair.

Induction of macrophage necrosis is a strategy used by virulent Mycobacterium tuberculosis (Mtb) to avoid innate host defense. In contrast, attenuated Mtb causes apoptosis, which limits bacterial replication and promotes T cell cross-priming by antigen-presenting cells. Here we show that Mtb infection causes plasma membrane microdisruptions. Resealing of these lesions, a process crucial for preventing necrosis and promoting apoptosis, required translocation of lysosomal and Golgi apparatus-derived vesicles to the plasma membrane. Plasma membrane repair depended on prostaglandin E(2) (PGE(2)), which regulates synaptotagmin 7 (Syt-7), the calcium sensor involved in the lysosome-mediated repair mechanism. By inducing production of lipoxin A(4) (LXA(4)), which blocks PGE(2) biosynthesis, virulent Mtb prevented membrane repair and induced necrosis. Thus, virulent Mtb impairs macrophage plasma membrane repair to evade host defenses.

The roles of small-molecule inflammatory mediators in rheumatoid arthritis.

Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation and joint destruction. Although great progress has been made in the treatment of RA with antagonists of pro-inflammatory cytokines such as TNF-α, IL-6 and IL-1, the disease remains refractory in some patients. Previous studies have found that small-molecule inflammatory mediators, such as prostaglandins, leukotrienes, reactive oxygen species, nitric oxide, lipoxins and platelet-activating factor, play a significant role in the development of RA. Such compounds help to induce, maintain or reduce inflammation and could therefore be potential therapeutic targets. In this review, we describe the roles of various classes of small-molecule inflammatory mediators in RA and discuss the effects of some drugs that modulate their activity. Many drugs targeting these mediators have demonstrated good efficacy in mouse models of RA but not in patients. However, it is clear that many small-molecule inflammatory mediators play key roles in the pathogenesis of RA, and a better understanding of the underlying molecular pathways may assist in the development of targeted therapies that are efficacious in RA patients.