5s-12r-18r-trihydroxy-6z-8e-10e-14z-16e-eicosapentaenoic-acid and Inflammation

Cardiovascular outcome trials on omega-3 fatty acids have generated contradictory results but indicate a dose-dependent beneficial effect of eicosapentaenoic acid (EPA). Beneficial cardiovascular effects of EPA may in addition to triglyceride lowering be mediated through alternative mechanisms of action. In this review, the link between EPA and a resolution of atherosclerotic inflammation is addressed. EPA is a substrate for the enzymatic metabolism into the lipid mediator resolvin E1 (RvE1), which activates the receptor ChemR23 to transduce an active resolution of inflammation. This has been shown to dampen the immune response and provide atheroprotective responses in different models. The intermediate EPA metabolite 18-HEPE emerges as a biomarker of EPA metabolism towards proresolving mediators in observational studies. Genetic variations within the EPA-RvE1-ChemR23 axis affecting the response to EPA may open up for precision medicine to identify responders and non-responders to EPA and fish oil supplementation. In conclusion, activation of the EPA-RvE1-ChemR23 axis towards a resolution of inflammation may contribute to beneficial effects in cardiovascular prevention.

Topics: Atherosclerosis; Eicosapentaenoic Acid; Humans; Inflammation

This review aims to discuss the existing evidence on the link between atherosclerosis and periodontitis by particularly presenting new findings that link the pathology and therapy of these diseases. Acute vascular ischemic events that can lead to stroke or myocardial infarction are initiated by inflammatory processes leading to rupture or erosion of plaques susceptible to thrombosis ("high risk" or "vulnerable"). These are highly inflamed plaques residing in the media and adventitia that may not be detected by angiography measurments of luminal narrowing. Statistically significant excess risk for atherosclerotic cardiovascular disease has been reported in persons with periodontitis independent of established risk factors. We hypothesized that the systemic pathologic links also represent potential therapeutic links.. We recently demonstrated that periodontal inflammation promotes atherosclerotic plaque inflammation and destabilization. As discrete pathological regions, these plaques with a high susceptibility to rupture can be imaged and differentiated from lower risk plaques. In cholesterol-fed rabbits with periodontal disease, circulating inflammatory mediators were also significantly elevated thereby contributing to "vulnerable blood," a systemic characteristic of high risk for cardiovascular events. New studies show that certain lipid mediators, including lipoxins and resolvins, are potent in preventing and possibly treating a number of inflammation-associated diseases, including periodontitis and vascular inflammation. The concept of the vulnerable patient and the pro-resolving approach open new terrain for discovery of paradigm-changing therapies for the prevention and treatment of two of the most common diseases of man. Importantly, lipoxins and resolvins are natural receptor agonists that do not exhibit the same pro-atherogenic side effects attributed to anti-inflammatory medications (e.g., NSAIDs) but rather coordinate resolution of inflammation and a return to homeostasis.

Topics: Animals; Anti-Inflammatory Agents; Atherosclerosis; Disease Models, Animal; Eicosapentaenoic Acid; Humans; Inflammation; Periodontitis; Plaque, Atherosclerotic; Rabbits; Thrombosis

Endogenous pain-inhibitory substances have rarely been found. A group of powerful pain suppressor molecules that are endogenously generated are now emerging: resolvins and related compounds including neuroprotectins and maresins. These molecules began to be unveiled in a series of inflammation studies more than a decade ago, rapidly shifting the paradigm that explains the mechanism for the inflammatory phase switch. The resolution phase was considered a passive process as proinflammatory mediators disappeared; it is now understood to be actively drawn by the actions of resolvins. Surprisingly, these substances potently affect the pain state. Although this research area is not fully matured, consistently beneficial outcomes have been observed in a various in vivo and in vitro pain models. Furthermore, multiple hypotheses on the neuronal and molecular mechanisms for alleviating pain are being tested, deriving inspiration from existing inflammation and pain studies. This paper serves as a brief summary of the proresolving roles of resolvins and related lipid mediators in inflammation and also as a review for accumulated information of their painkilling actions. This also includes potential receptor-mediated mechanisms and discusses future scientific perspectives. Further diverse approaches will help to construct a hidden axis of natural protection principles and establish proofs of concept for pain relief.

Topics: Calcium Channels; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Nerve Tissue Proteins; Pain; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Resolvin E1 (RvE1) is a recently discovered lipid-derived mediator that is endogenously synthesized from the polyunsaturated fatty acid eicosapentaenoic acid. RvE1 is locally generated in response to inflammation where it enhances the resolution phase of inflammation by diminishing neutrophil chemotaxis and by enhancing nonphlogistic macrophage-directed clearance of apoptotic neutrophils. RvE1 was also found to be effective in preventing and restoring bone loss in the inflammatory bone disease periodontitis. This review examines experimental evidence on RvEl's actions in bone. Current data indicate that in addition to anti-inflammatory actions, RvE1 also directly acts on bone cells and promotes bone preservation.

Topics: Animals; Bone and Bones; Bone Remodeling; Bone Resorption; Eicosapentaenoic Acid; Humans; Inflammation; Lipid Metabolism

Resolvins, including D and E series resolvins, are endogenous lipid mediators generated during the resolution phase of acute inflammation from the omega-3 polyunsaturated fatty acids docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). Resolvins have potent anti-inflammatory and pro-resolution actions in several animal models of inflammation. Recent findings also demonstrate that resolvin E1 and resolvin D1 can each potently dampen inflammatory and postoperative pain. This review focuses on the mechanisms by which resolvins act on their receptors in immune cells and neurons to normalize exaggerated pain via regulation of inflammatory mediators, transient receptor potential (TRP) ion channels, and spinal cord synaptic transmission. Resolvins may offer novel therapeutic approaches for preventing and treating pain conditions associated with inflammation.

Topics: Analgesics; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Neurons; Pain; Pain, Postoperative

Asthma is characterized by airway hyperresponsiveness and chronic airway inflammation. Inflammatory cells, including eosinophils and lymphocytes, infiltrate peribronchial tissue in patients with asthma. Resolvin E1 (RvE1) is an anti-inflammatory lipid mediator derived from the omega-3 fatty acid, eicosapentaenoic acid, and has been shown to be involved in resolving inflammation. Although little is known about the actions of RvE1 in the resolution of inflammation due to asthma, recent studies in a mouse model have shown the possibilities of RvE1 in asthma.. We review the current understanding of the mechanism of RvE1 action in connection with asthma pathogenesis and treatment.. Findings provide evidence for the use of RvE1 as a pivotal counter-regulatory signal in allergic inflammation and offer the possibility of novel multi-pronged therapeutic approaches for human asthma.

Topics: Adult; Animals; Anti-Asthmatic Agents; Asthma; CD59 Antigens; Child; Dietary Fats; Drug Evaluation, Preclinical; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Humans; Inflammation; Leukotriene Antagonists; Lipoxins; Mice; Receptors, Leukotriene B4

Recently, lipoxins (LXs) and resolvins (Rvs) have become the topic of intense interest because of expanding views of their action, particularly in chronic disorders where unresolved inflammation is a key factor leading to colon carcinogenesis. Rvs are biosynthesized from omega-3 fatty acids eicosapentanoic acid (EPA) and docosahexaenoic acid (DHA) via cyclooxygenase-2/lipoxygenase (COX-2/LOX) pathways; Rvs are shown to dramatically reduce dermal inflammation, peritonitis, dendritic cell migration, and interleukin production. This explains that dietary supplementation of omega-3 fatty acids generates potent local endogenous mediators that control inflammation. LXs are biosynthesized from COX-2/LOX pathways. Metabolites of 15-LOX-1 and 2 are anti-tumorigenic; similarly, 15-epi-LXA(4) synthesized during COX-2 acetylation by low doses of aspirin too possesses anti-tumorigenic effects. Acetylating nonsteroidal anti-inflammatory drugs (NSAIDs), like aspirin, switches COX-2 from forming PGE(2) (promoting tumorigenesis) to 15-epi-LXA(4) (antitumorigenesis). LXs and Rvs are endogenously generated during the spontaneous resolution phase. These newly identified LXs and Rvs have proved to be potent regulators of both leukocytes and cytokine productions, thereby regulating the events of interest in inflammation and resolution. In light of existing knowledge on interconnected pathways of pro-inflammatory mediators (leukotrienes, chemokines (IL8, SDF-1 alpha, MIP-1 alpha, MCP-1,2 etc), and cytokines (IL3, IL6, IL12, IL-1 beta, GM-CSF, B94, TNF-alpha etc)), the anti-inflammatory properties of pro-resolving mediators in preventing chronic inflammation which leads to carcinogenesis needs further understanding. In this review, we explore the mechanisms that trigger formation of LXs and Rvs, to highlight the relative importance of LXs and Rvs in carcinogenesis in relation to pro-inflammatory mediators.

Topics: Arachidonate 15-Lipoxygenase; Colonic Neoplasms; Cyclooxygenase 2; Dinoprostone; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Lipoxins; Models, Biological

Research on the formation of novel enzymatic oxygenation products derived from the omega-3 fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) has revealed the endogenous formation of several novel autacoids that have been termed resolvins and protectins. The elucidation of the chemical structures of resolvins and protectins, and the assessment of their endogenous functions, are providing a new understanding of the role of endogenous omega-3 fatty acid-derived lipid mediators in tissue protection, counteraction of inflammation and the activation of inflammation resolution. This review emphasizes the structural aspects of resolvin biosynthesis and metabolic inactivation, which are of central importance for understanding the current and future development of therapeutically relevant, stable analogs that may activate inflammation resolution.

Topics: Animals; Anti-Inflammatory Agents; Aspirin; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Lipoxins; Molecular Structure; Signal Transduction; Structure-Activity Relationship

Inflammation is a defensive response to injury and infection, but excessive or inappropriate inflammation contributes to a range of acute and chronic human diseases. Clinical assessment of dietary supplementation of omega-3 polyunsaturated fatty acids (PUFA) including eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) indicate their beneficial impact on human diseases in which inflammation is suspected as a key component of the pathogenesis. Although the mechanism of EPA and DHA action is still not fully defined in molecular terms, recent studies have revealed that, during the course of acute inflammation, omega-3 PUFA-derived mediators including resolvins and protectins with potent anti-inflammatory and pro-resolving properties are produced. In this review, we provide an overview of the formation and actions of EPA-derived anti-inflammatory lipid mediator resolvin E1.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Aspirin; Blood Platelets; Cell Adhesion Molecules; Docosahexaenoic Acids; Eicosapentaenoic Acid; Exudates and Transudates; Fatty Acids, Omega-3; Humans; Inflammation; Mononuclear Phagocyte System; Phagocytes

It has become clear in recent years that periodontitis is an inflammatory disease initiated by oral microbial biofilm. This distinction implies that it is the host response to the biofilm that destroys the periodontium in the pathogenesis of the disease. As our understanding of pathways of inflammation has matured, a better understanding of the molecular basis of resolution of inflammation has emerged. Resolution of inflammation is an active, agonist-mediated, well-orchestrated return of tissue homeostasis. There is an important distinction between anti-inflammation and resolution; anti-inflammation is pharmacologic intervention in inflammatory pathways, whereas resolution is biologic pathways restoring homeostasis. A growing body of research suggests that chronic inflammatory periodontal disease involves a failure of resolution pathways to restore homeostasis. This article reviews the resolution of inflammation in the context of periodontal disease and the potential for the modification of resolution pathways for the prevention and treatment of periodontal diseases. Proof-of-concept studies in the 1980s demonstrated that pharmacologic anti-inflammation prevented and slowed the progression of periodontal diseases in animals and man. However, the side-effect profile of such therapies precluded the use of non-steroidal anti-inflammatory drugs or other enzyme inhibitors or receptor antagonists in periodontal therapy. The isolation and characterization of resolving agonist molecules has opened a new area of research using endogenous lipid mediators of resolution as potential therapeutic agents for the management of inflammatory periodontitis. Work in animal models of periodontitis has revealed the potential of this therapeutic approach for its prevention and treatment and forced the reconsideration of our understanding of the pathogenesis of human periodontal diseases.

Topics: Animals; Anti-Inflammatory Agents; Biofilms; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Lipoxins; Periodontal Diseases; Periodontitis

The physiological resolution of a well-orchestrated inflammatory response is essential to maintain homeostasis. Therefore, gaining a comprehensive understanding in molecular terms of the events that direct the termination of acute inflammation is imperative. Recently, new families of local-acting mediators were discovered that are biosynthesized from the essential fatty acids eicosapentaenoic acid and docosahexaenoic acid. These new chemical mediators are endogenously generated in inflammatory exudates collected during the resolution phase, and were termed resolvins and protectins because specific members of these families control the magnitude and duration of inflammation in animals. In addition, recent results indicate novel actions of resolvins and protectins in removing chemokines ferried from the tissue by apoptotic neutrophils and T cells during resolution. Here, we review recent advances on the biosynthesis and actions of these novel anti-inflammatory and proresolving mediators.

Topics: Acute Disease; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Multigene Family

Topics: Animals; CD59 Antigens; Docosahexaenoic Acids; Drug Design; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Homeostasis; Humans; Inflammation; Inflammation Mediators; Lipid Metabolism

Topics: Alveolar Bone Loss; Animals; Anti-Inflammatory Agents; Aspirin; Biofilms; Bone Regeneration; Disease Susceptibility; Eicosapentaenoic Acid; Humans; Inflammation; Lipoxins; Periodontitis

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.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acids; Aspirin; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Lipid Metabolism; Lipoxins; Signal Transduction

Resolvins and protectins are new families consisting of distinct chemical series of lipid-derived mediators, each with unique structures and apparent complementary anti-inflammatory actions. Both families of compounds, Rv and protectins, are also generated when aspirin is given in mammalian systems in their respective epimeric forms. The resolvins and protectins each dampen inflammation and PMN-mediated injury from within, which is a key culprit in many common human diseases. The results of these initial studies underscore the roles of resolvins and protectins in inflammation resolution as well as catabasis and spotlight the therapeutic potential for this new arena of immunomodulation and host protection. It is likely that the resolvins, protectins, and their AT-related forms may play roles in other tissues and organs. Moreover, it is noteworthy that fish (eg, trout) generate lipoxygenase products such as LXAs from endogenous EPA and also biosynthesize RvDs and protectins from endogenous DHA. Taken together, these findings suggest that these novel lipid mediators (eg, resolvins and protectins) are conserved in evolution as self-protective and host-protective chemical mediators. In view of the essential roles of DHA and EPA in human biology and medicine uncovered to date, the physiologic relevance of the resolvins and protectins is likely to extend beyond our current appreciation.

Topics: Animals; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Aspirin; CD59 Antigens; Complement Inactivating Agents; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Humans; Inflammation; Neuroprotective Agents

Inflammation plays a significant role in carcinogenesis and tumor growth. The current study was designed to test the hypothesis that resolvin E1 (RvE1) and overexpression of the receptor for RvE1 (ERV1) will prevent and/or reverse tumor generation in a gain-of-function mouse model of tumor seeding with lung cancer cells. To measure the impact of enhanced resolution of inflammation on cancer pathogenesis, ERV1-overexpressing transgenic (TG) and wild-type FVB mice were given an injection of 1 × 10

Topics: Angiopoietins; Animals; Cisplatin; Cyclooxygenase 2; Cytokines; Disease Models, Animal; Eicosapentaenoic Acid; Heterografts; Inflammation; Ki-67 Antigen; Lung Neoplasms; Mice; NF-kappa B; Vascular Endothelial Growth Factor A

Resolvin E1 (RvE1) is a potent anti-inflammatory and proresolving mediator derived from omega-3 eicosapentaenoic acid generated during the resolution phase of inflammation. RvE1 possesses a unique structure and counterregulatory actions that stop human polymorphonuclear leukocyte (PMN) transendothelial migration and PMN infiltration in several murine inflammatory models. To examine the mechanism(s) underlying anti-inflammatory actions on PMNs, we prepared [(3)H]RvE1 and characterized its interactions with human PMN. Results with membrane fractions of human PMN demonstrated specific binding with a K(d) of 48.3 nM. [(3)H]RvE1 specific binding to human PMN was displaced by leukotriene B(4) (LTB(4)) and LTB(4) receptor 1 (BLT1) antagonist U-75302, but not by chemerin peptide, a ligand specific for another RvE1 receptor ChemR23. Recombinant human BLT1 gave specific binding with [(3)H]RvE1 with a K(d) of 45 nM. RvE1 selectively inhibited adenylate cyclase with BLT1, but not with BLT2. In human PBMC, RvE1 partially induced calcium mobilization, and blocked subsequent stimulation by LTB(4). RvE1 also attenuated LTB(4)-induced NF-kappaB activation in BLT1-transfected cells. In vivo anti-inflammatory actions of RvE1 were sharply reduced in BLT1 knockout mice when given at low doses (100 ng i.v.) in peritonitis. In contrast, RvE1 at higher doses (1.0 mug i.v.) significantly reduced PMN infiltration in a BLT1-independent manner. These results indicate that RvE1 binds to BLT1 as a partial agonist, potentially serving as a local damper of BLT1 signals on leukocytes along with other receptors (e.g., ChemR23-mediated counterregulatory actions) to mediate the resolution of inflammation.

Topics: Animals; Calcium Signaling; Cell Movement; Chemokines; Dose-Response Relationship, Drug; Eicosapentaenoic Acid; Fatty Alcohols; Glycols; Humans; Inflammation; Intercellular Signaling Peptides and Proteins; Ligands; Mice; Mice, Knockout; Neutrophils; Peptides; Receptors, Chemokine; Receptors, Leukotriene B4

Cardiovascular disease (CVD) and periodontal disease have a common pathogenesis with inflammation and resolution steps. Although the relationships among periodontal disease, CVD, and specialized pro-resolving lipid mediator (sPRLM)s are well known, there is no study about the combined effects of cardiovascular and periodontal treatments on sPRLM levels. It was aimed to evaluate the effects of periodontal and cardiovascular therapies on sPRLMs (lipoxin A4, protectin (PD)1, resolvin (Rv) E1, RvD1, and maresin (MaR)1) in patients with CVD and periodontal disease.. This observational study consisted of fifty-five patients with CVD and mild or moderate periodontitis. The clinical periodontal parameters (plaque index, gingival index, probing pocket depth, percentage of bleeding on probing, and clinical attachment level) and blood and unstimulated total saliva samples were obtained at baseline, at 3 months (following only cardiovascular therapy), and at 6 months (following cardiovascular and periodontal therapies). The blood count and serum levels of cardiometabolic biomarkers (white blood cell, neutrophil/lymphocyte, serum total cholesterol (TC), triglyceride, and low and high-density lipoprotein (HDL) levels) were evaluated. sPRLMs were evaluated by ELISA.. There were significant decreases in body mass index, clinical periodontal parameters, WBC, LDL, PD1, and RvD1 at 6 months compared to baseline. The decreases in TC/HDL, RvE1, and MaR1 levels were significant at 3 and 6 months compared to baseline (p < 0.05).. The combination of cardiovascular and periodontal treatments leads to significant reductions in clinical periodontal and cardiometabolic parameters and sPRLMs.. Our report, which is the first in their field, suggested that cardiovascular and periodontal therapies provide an important contribution via decreasing the periodontal and atherosclerotic inflammation modulating sPRLMs. This finding will be a big step toward increasing the quality of life in these patients by drawing attention to importance of public health associated with oral hygiene, periodontal health, and systemic phase of periodontal treatment.

Topics: Cardiovascular Diseases; Eicosapentaenoic Acid; Humans; Inflammation; Periodontal Diseases; Quality of Life

Persistent and chronic unresolved inflammation exerts a critical role in developing atherosclerosis; however, mechanisms that prevent the resolution of inflammation in atherosclerosis are poorly delineated. This study aims to evaluate the serum levels of inflammatory high-sensitivity C-reactive protein (hsCRP), pro-inflammatory leukotriene B4 (LTB4), besides anti-inflammatory compounds, including eicosapentaenoic acid (EPA) and its derivative resolvin E1 (RvE1) in patients with atherosclerosis. Thirty-four atherosclerosis patients and thirty-two age- and sex-matched healthy individuals were included in this study. The serum levels of hsCRP, LTB4, EPA, and RvE1 were measured using the enzyme-linked immunosorbent assay (ELISA) technique. Our results showed that the hsCRP serum levels in the three-vessel disease (3VD) subgroup of patients are significantly lower than those in the mild and single-vessel disease (SVD) subgroups (P < 0.05). Besides, the serum levels of LTB4 were meaningfully greater in patients with atherosclerosis compared to healthy controls (P < 0.05). Also, the serum EPA and RvE1 levels were significantly higher in patients than in controls (P < 0.01 and P < 0.05, respectively). However, the ratio of RvE1 to LTB4 (RvE1:LTB4) in patients was significantly reduced to that in controls (P < 0.0001). These findings illustrate that imbalanced pro-resolving RvE1 and pro-inflammatory LTB4 might contribute to failing vascular inflammation resolution and subsequent progression toward chronic inflammation in atherosclerosis.

Topics: Atherosclerosis; C-Reactive Protein; Eicosapentaenoic Acid; Humans; Inflammation; Leukotriene B4

Inflammation plays a critical role in the development of hypertension and vascular remodeling. Resolvin E1 (RvE1), as one of the specialized proresolving lipid mediators, promotes inflammation resolution by binding with a G protein-coupled receptor, ChemR23 (chemerin receptor 23). However, whether RvE1/ChemR23 regulates hypertension and vascular remodeling is unknown.. Hypertension in mice was induced by Ang II (angiotensin II) infusion (750 ng/kg per minute), and RvE1 (2 µg/kg per day) was administered through intraperitoneal injection. Loss of ChemR23 was achieved by mice receiving intravenous injection of adeno-associated virus 9-encoding shRNA against ChemR23.. Aortic ChemR23 expression was increased in Ang II-induced hypertensive mice and that ChemR23 was mainly expressed on vascular smooth muscle cells (VSMCs). RvE1 lowered blood pressure, reduced aortic media thickness, attenuated aortic fibrosis, and mitigated VSMC phenotypic transformation and proliferation in hypertensive mice, which were all reversed by the knockdown of ChemR23. Moreover, RvE1 reduced the aortic infiltration of macrophages and T cells, which was also reversed by ChemR23 knockdown. RvE1 inhibited Ccl5 expression in VSMCs via the AMPKα (AMP-activated protein kinase α)/Nrf2 (nuclear factor E2-related factor 2)/canonical NF-κB (nuclear factor κB) pathway, thereby reducing the infiltration of macrophages and T cells. The AMPKα/Nrf2 pathway also mediated the effects of RvE1 on VSMC phenotypic transformation and proliferation. In patients with hypertension, the serum levels of RvE1 and other eicosapentaenoic acid-derived metabolites were significantly decreased.. RvE1/ChemR23 ameliorated hypertension and vascular remodeling by activating AMPKα/Nrf2 signaling, which mediated immune cell infiltration by inhibiting the canonical NF-κB/Ccl5 pathway, and regulated VSMC proliferation and phenotypic transformation. RvE1/ChemR23 may be a potential therapeutic target for hypertension.

Topics: Angiotensin II; Animals; Chemokines; Eicosapentaenoic Acid; Humans; Hypertension; Inflammation; Intercellular Signaling Peptides and Proteins; Mice; NF-E2-Related Factor 2; NF-kappa B; Peptide Hormones; Vascular Remodeling

Vital pulp therapy and root canal therapy (RCT) are the dominant treatment for irreversible pulpitis. While the success rate of these procedures is favorable, they have some limitations. For instance, RCT leads to removing significant dentin in the coronal third of the tooth that increases root-fracture risk, which forces tooth removal. The ideal therapeutic goal is dental pulp regeneration, which is not achievable with RCT. Specialized proresolving mediators (SPMs) are well known for inflammatory resolution. The resolution of inflammation and tissue restoration or regeneration is a dynamic and continuous process. SPMs not only have potent immune-modulating functions but also effectively promote tissue homeostasis and regeneration. Resolvins have been shown to promote dental pulp regeneration. The purpose of this study was to explore further the cellular target of Resolvin E1 (RvE1) therapy in dental pulp regeneration and the impact of RvE1 in infected pulps. We investigated the actions of RvE1 on experimentally exposed pulps with or without microbial infection in an

Topics: Animals; Axin Protein; Bacteria; Dental Pulp; Inflammation; Mice; Periapical Periodontitis; Pulpitis; Regeneration

Expression status of pro-resolvin lipid mediators (PLM) and receptors in the post-Coronary artery bypass grafting (CABG) coronary arteries are largely unknown. Here, we aim to investigate the expression of the enzymes involved in PLM synthesis and their receptors in the atherosclerotic post-CABG swine (AS) left anterior descending (LAD) compared to without CABG (LAD-AS), and in isolated coronary artery smooth muscle cells (CASMCs) cultured under ischemia.. The arteries of interest were harvested from post-CABG atherosclerotic swine and the histomorphology and the expression status of key PLM mediators were quantified using immunostaining. Smooth muscle cells (SMCs) were cultured under ischemia and confirmed the expression on PLM mediators at transcript and protein level.. The histomorphometric analysis revealed considerable alterations in the tissue architecture in LAD-CABG and LAD-AS arteries compared to control. PLM synthetic enzyme 5-lipoxygenases (5LO) was significantly upregulated in LAD-CABG and LAD-AS whereas the other enzymes including 12LO, 15LO, and cyclooxygenase-2, and the receptors including Chemokine like receptor 1 (ChemR23), 7-transmembrane G-protein coupled receptor-18 (GPCR18), GPCR120 were decreased in LAD-CABG than control. LO enzymes and PLM receptors were upregulated in ischemic CASMCs with respect to control. Western blot showed the upregulation of 5LO, and ChemR23. Additionally, higher level of resolvin-E1 (RvE1) was observed in ischemic control CASMCs which was decreased following reperfusion.. These findings suggest that the CASMCs withstand the ischemia-triggered proinflammatory episodes by increasing the secretion of RvE1 mediated through 5LO and ChemR23 signaling.

Topics: Animals; Arachidonate 5-Lipoxygenase; Chemokines; Coronary Artery Bypass; Coronary Vessels; Eicosapentaenoic Acid; Inflammation; Ischemia; Swine

Endothelial cell senescence contributes to chronic inflammation and endothelial dysfunction, while favoring cardiovascular disorders and frailty. Senescent cells acquire a pro-inflammatory secretory phenotype that further propagates inflammation and senescence to neighboring cells. Cell senescence can be provoked by plethora of stressors, including inflammatory molecules and chemotherapeutic drugs. Doxorubicin (Doxo) is a powerful anthracycline anticancer drug whose clinical application is constrained by a dose-limiting cardiovascular toxicity. We here investigated whether cell senescence can contribute to the vascular damage elicited by Doxo. In human umbilical vein endothelial cells (HUVEC) cultures, Doxo (10-100 nM) increased the number of SA-β-gal positive cells and the levels of γH2AX, p21 and p53, used as markers of senescence. Moreover, we identified Doxo-induced senescence to be mediated by the nucleotide-binding domain-like receptor protein 3 (NLRP3) inflammasome, a key player of the immune innate system capable of releasing interleukin (IL)-1β. In fact, IL-1β itself mimicked the stimulatory action of Doxo on both NLRP3 activation and cellular senescence, while the pharmacological blockade of IL-1 receptors markedly attenuated the pro-senescence effects of Doxo. In search of additional pharmacological strategies to attenuate Doxo-induced endothelial senescence, we identified resolvin E1 (RvE1), an endogenous pro-resolving mediator, as capable of reducing cell senescence induced by both Doxo and IL-1β by interfering with the increased expression of pP65, NLRP3, and pro-IL-1β proteins and with the formation of active NLRP3 inflammasome complexes. Overall, RvE1 and the blockade of the NLRP3 inflammasome-IL-1β axis may offer a novel therapeutic approach against Doxo-induced cardiovascular toxicity and subsequent sequelae.

Topics: Cellular Senescence; Doxorubicin; Drug Interactions; Eicosapentaenoic Acid; Human Umbilical Vein Endothelial Cells; Humans; Inflammasomes; Inflammation; Interleukin-1beta; NLR Family, Pyrin Domain-Containing 3 Protein

Resolvins (RvD1, RvD2 and RvE1) are endogenous anti-inflammatory lipid mediators that display potent analgesic properties in somatic pain by modulating transient receptor potential vanilloid 1 (TRPV1) activation. To what extent these molecules could also have a beneficial effect on TRPV1 sensitisation and visceral hypersensitivity (VHS), mechanisms involved in IBS, remains unknown.. The effect of RvD1, RvD2 and RvE1 on TRPV1 activation and sensitisation by histamine or IBS supernatants was assessed on murine dorsal root ganglion (DRG) neurons using live Ca. RvD1, RvD2 and RvE1 prevented histamine-induced TRPV1 sensitisation in DRG neurons at doses devoid of an analgesic effect. Of note, RvD2 also reversed TRPV1 sensitisation by histamine and IBS supernatant. This effect was blocked by the G protein receptor 18 (GPR18) antagonist O-1918 (3-30 µM) and by pertussis toxin. In addition, RvD2 reduced the capsaicin-induced Ca. Our data suggest that RvD2 and GPR18 agonists may represent interesting novel compounds to be further evaluated as treatment for IBS.

Topics: Adult; Animals; Capsaicin; Disease Models, Animal; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enterobacteriaceae Infections; Female; Ganglia, Spinal; Histamine; Humans; Hypersensitivity; Inflammation; Irritable Bowel Syndrome; Male; Mice; Middle Aged; Neurons; Rats; Receptors, Cannabinoid; TRPV Cation Channels

Cardiac fibroblasts (CFs) have a key role in the inflammatory response after cardiac injury and are necessary for wound healing. Resolvins are potent agonists that control the duration and magnitude of inflammation. They decrease mediators of pro-inflammatory expression, reduce neutrophil migration to inflammation sites, promote the removal of microbes and apoptotic cells, and reduce exudate. However, whether resolvins can prevent pro-inflammatory-dependent effects in CFs is unknown. Thus, the present work was addressed to study whether resolvin D1 and E1 (RvD1 and RvE1) can prevent pro-inflammatory effects on CFs after lipopolysaccharide (LPS) challenge. For this, CFs were stimulated with LPS, in the presence or absence of RvD1 or RvE1, to analyze its effects on intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion protein 1 (VCAM-1), monocyte adhesion and the cytokine levels of tumor necrosis factor alpha (TNF-α), interleukin-6(IL-6), interleukin-1beta (IL-1β), monocyte chemoattractant protein-1 (MCP-1) and interleukin-10 (IL-10). Our results showed that CFs are expressing ALX/FPR2 and ChemR23, RvD1 and RvE1 receptors, respectively. RvD1 and RvE1 prevent the increase of ICAM-1 and VCAM-1 protein levels and the adhesion of spleen mononuclear cells to CFs induced by LPS. Finally, RvD1, but not RvE1, prevents the LPS-induced increase of IL-6, MCP-1, TNF-α, and IL-10. In conclusion, our findings provide evidence that in CFs, RvD1 and RvE1 might actively participate in the prevention of inflammatory response triggered by LPS.

Topics: Animals; Cell Movement; Cytokines; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fibroblasts; Gene Expression Regulation; Heart Injuries; Humans; Inflammation; Interleukin-1beta; Lipopolysaccharides; Neutrophils; Rats; Tumor Necrosis Factor-alpha; Vascular Cell Adhesion Molecule-1; Wound Healing

Unresolved inflammation and tissue destruction are considered to underlie the failure of dental pulp repair. As key mediators of the injury response, dental pulp stem cells (DPSCs) play a critical role in pulp tissue repair and regeneration. Resolvin E1 (RvE1), a major dietary omega-3 polyunsaturated fatty-acid metabolite, is effective in resolving inflammation and activating wound healing. However, whether RvE1 facilitates injured pulp-tissue repair and regeneration through timely resolution of inflammation and rapid mobilization of DPSCs is unknown. Therefore, we established a pulp injury model and investigated the effects of RvE1 on DPSC-mediated inflammation resolution and injured pulp repair.. A pulp injury model was established using 8-week-old Sprague-Dawley rats. Animals were sacrificed on days 1, 3, 7, 14, 21, and 28 after pulp capping with a collagen sponge immersed in PBS with RvE1 or PBS. Hematoxylin-eosin and Masson's trichrome staining, immunohistochemistry, and immunohistofluorescence were used to evaluate the prohealing properties of RvE1. hDPSCs were incubated with lipopolysaccharide (LPS) to induce an inflammatory response, and the expression of inflammatory factors after RvE1 application was measured. Effects of RvE1 on hDPSC proliferation, chemotaxis, and odontogenic differentiation were evaluated by CCK-8 assay, transwell assay, alkaline phosphatase (ALP) staining, alizarin red staining, and quantitative PCR, and possible signaling pathways were explored using western blotting.. In vivo, RvE1 reduced the necrosis rate of damaged pulp and preserved more vital pulps, and promoted injured pulp repair and reparative dentin formation. Further, it enhanced dentin matrix protein 1 and dentin sialoprotein expression and accelerated pulp inflammation resolution by suppressing TNF-α and IL-1β expression. RvE1 enhanced the recruitment of CD146. RvE1 promotes pulp inflammation resolution and dentin regeneration and positively influences the proliferation, chemotaxis, and differentiation of LPS-stimulated hDPSCs. This response is, at least partially, dependent on AKT, ERK, and rS6-associated signaling in the inflammatory microenvironment. RvE1 has promising application potential in regenerative endodontics.

Topics: Animals; Cell Differentiation; Cell Proliferation; Cells, Cultured; Dental Pulp; Dentin; Eicosapentaenoic Acid; Inflammation; Rats; Rats, Sprague-Dawley; Stem Cells

Agricultural workers, especially those who work in swine confinement facilities, are at increased risk for developing pulmonary diseases including asthma, chronic obstructive pulmonary disease, and chronic bronchitis due to exposures to fumes, vapors, and organic dust. Repetitive exposure to agricultural dust leads to unresolved inflammation, a common underlying mechanism that worsens lung disease. Besides occupational exposure to dusts, diet also significantly contributes to inflammation and disease progression. Since DHA (docosahexaenoic acid), a polyunsaturated omega-3 fatty acid and its bioactive metabolites have key roles in inflammation resolution, we rationalized that individuals chronically exposed to organic dusts can benefit from dietary modifications. Here, we evaluated the role of DHA in modifying airway inflammation in a murine model of repetitive exposure to an aqueous extract of agricultural dust (three-week exposure to swine confinement dust extract, HDE) and after a one-week resolution/recovery period. We found that mice fed a high DHA diet had significantly increased bronchoalveolar lavage fluid (BALF) levels of DHA-derived resolvins and lower TNFα along with altered plasma levels of endocannabinoids and related lipid mediators. Following the one-week recovery we identified significantly reduced BALF cellularity and cytokine/chemokine release along with increased BALF amphiregulin and resolvins in DHA diet-fed versus control diet-fed mice challenged with HDE. We further report observations on the effects of repetitive HDE exposure on lung Ym1+ and Arg-1+ macrophages. Overall, our findings support a protective role for DHA and identify DHA-derived resolvins and endocannabinoids among the potential mediators of DHA in altering airway inflammation in chronic agricultural dust exposure.

Topics: Agricultural Workers' Diseases; Animals; Bronchoalveolar Lavage Fluid; Diet; Disease Models, Animal; Docosahexaenoic Acids; Dust; Eicosapentaenoic Acid; Endocannabinoids; Fatty Acids, Unsaturated; Inflammation; Inhalation Exposure; Lung; Macrophages, Alveolar; Male; Mice; Mice, Inbred C57BL; Respiratory Tract Diseases; Swine; Tumor Necrosis Factor-alpha

Chronic inflammatory diseases, including diabetes and cardiovascular disease, are heterogeneous and often co-morbid, with increasing global prevalence. Uncontrolled type 2 diabetes (T2D) can result in severe inflammatory complications. As neutrophils are essential to normal and aberrant inflammation, we conducted RNA-seq transcriptomic analyses to investigate the association between neutrophil gene expression and T2D phenotype. As specialized pro-resolving lipid mediators (SPM) act to resolve inflammation, we further surveyed the impact of neutrophil receptor binding SPM resolvin E1 (RvE1) on isolated diabetic and healthy neutrophils.. Cell isolation and RNA-seq analysis of neutrophils from N = 11 T2D and N = 7 healthy individuals with available clinical data was conducted. Additionally, cultured neutrophils (N = 3 T2D, N = 3 healthy) were perturbed with increasing RvE1 doses (0 nM, 1 nM, 10 nM, or 100 nM) prior to RNA-seq. Data was evaluated through a bioinformatics pipeline including pathway analysis and post hoc false discovery rate (FDR)-correction.. We observed significant differential expression of 50 genes between T2D and healthy neutrophils (p < 0.05), including decreased T2D gene expression in inflammatory- and lipid-related genes SLC9A4, NECTIN2, and PLPP3 (p < 0.003). RvE1 treatment induced dose-dependent differential gene expression (uncorrected p < 0.05) across groups, including 59 healthy and 216 T2D neutrophil genes. Comparing T2D to healthy neutrophils, 1097 genes were differentially expressed across RvE1 doses, including two significant genes, LILRB5 and AKR1C1, involved in inflammation (p < 0.05).. The neutrophil transcriptomic database revealed novel chronic inflammatory- and lipid-related genes that were differentially expressed between T2D cells when compared to controls, and cells responded to RvE1 dose-dependently by gene expression changes. Unraveling the mechanisms regulating abnormalities in diabetic neutrophil responses could lead to better diagnostics and therapeutics targeting inflammation and inflammation resolution.

Topics: 20-Hydroxysteroid Dehydrogenases; Adult; Aged; Antigens, CD; Cells, Cultured; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Female; Gene Expression Profiling; Gene Expression Regulation; Humans; Inflammation; Leukocyte Immunoglobulin-like Receptor B1; Male; Middle Aged; Nectins; Neutrophils; Phosphatidate Phosphatase; Sequence Analysis, RNA; Sodium-Hydrogen Exchangers; Transcriptome

Rheumatoid arthritis (RA) is a disease in which joint inflammation is at the forefront but the whole body is affected, and prevention of inflammation is the main treatment approach. Lipoxins (LXs) and resolvins (Rvs) are critical molecules in the resolution of inflammation. In this study, we aimed to investigate the role of LXs and Rvs in the RA pathogenesis. To this end, we measured the LXA 4, RvD 1, RvE 1 levels, and inflammatory cytokines and chemokines IL-6, IL-8, IL-10, IL-17a, IL-22 and MCP-1 in patients with RA and healthy individuals. We found that the LXA4, RvD1, RvE1 levels of the active RA cases were significantly lower than in remission RA and healthy individuals, but the levels of inflammatory cytokines and chemokines were significantly higher. The decreases in LXs and Rvs were independent of disease activity, suggesting that there might be an impairment of LX and Rvs synthesis or catabolism in patients with RA.

Topics: Adult; Aged; Arthritis, Rheumatoid; Cytokines; Disease Progression; Docosahexaenoic Acids; Eicosapentaenoic Acid; Female; Humans; Inflammation; Inflammation Mediators; Lipid Metabolism; Lipoxins; Male; Middle Aged

In addition to the direct effects of irradiation, the induced inflammatory response may play an important role in the damage to the inner ear caused by radiotherapy for the treatment of head and neck cancers. Resolvin E1 (RvE1) has anti-inflammatory activity, acting by reducing neutrophil infiltration and proinflammatory cytokine expression. Therefore, in this study we sought to confirm whether the inflammation induced by irradiation was involved in damage to the inner ear after radiotherapy and to investigate the protective effect and underlying mechanism of RvE1 using mouse models.. A dose of RvE1 was delivered by intraperitoneal injection to mice before irradiation. Changes in the auditory brainstem response (ABR), relative balance ability, inner ear morphology and the expression levels of inflammatory factors in the inner ear were analyzed on days 7 and 14 after irradiation and compared among different experimental groups.. Changes of ABR and relative balance ability showed the inner functions of experimental mice presented severe damage after irradiation, but the damage was significantly alleviated after RvE1 pretreatment compared to irradiation alone. Morphological analysis of the inner ear showed severe damage to the cochlea and vestibule after irradiation. In contrast, damage to the cochlea and vestibule was significantly reduced in the RvE1-pretreated group compared to that in the irradiation alone group. Along with these functional and morphological changes, the mRNA expression level of anti-inflammatory factors interleukin-2 was significantly increased, while those of proinflammatory factors interleukin-6 and tumor necrosis factor-α were significantly decreased in the inner ear of mice after RvE1 pretreatment compared to irradiation alone.. We believe that inflammation induced by irradiation is involved in the damage to the inner ear caused by radiotherapy, and that RvE1 reduces the damage caused by irradiation to the inner ear by regulating the induced inflammatory response.

Topics: Animals; Ear, Inner; Eicosapentaenoic Acid; Female; Inflammation; Mice; Mice, Inbred C57BL; Radiation-Protective Agents; X-Rays

Topics: Cells, Cultured; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Periodontal Ligament; Regeneration; Stem Cells

Tendon stromal cells isolated from patients with chronic shoulder rotator cuff tendon tears have dysregulated resolution responses. Current therapies do not address the biological processes concerned with persistent tendon inflammation; therefore, new therapeutic approaches that target tendon stromal cells are required. We examined whether two specialized proresolving mediators (SPMs), lipoxin B4 (LXB4) and resolvin E1 (RvE1), modulate the bioactive lipid mediator profiles of IL-1β-stimulated tendon cells derived from patients with shoulder tendon tears and healthy volunteers. We also examined whether LXB4 or RvE1 treatments moderated the proinflammatory phenotype of tendon tear stromal cells. Incubation of IL-1β-treated patient-derived tendon cells in LXB4 or RvE1 up-regulated concentrations of SPMs. RvE1 treatment of diseased tendon stromal cells increased 15-epi-LXB4 and regulated postaglandin F2α. LXB4 or RvE1 also induced expression of the SPM biosynthetic enzymes 12-lipoxygenase and 15-lipoxygenase. RvE1 treatment up-regulated the proresolving receptor human resolvin E1 compared with vehicle-treated cells. Incubation in LXB4 or RvE1 moderated the proinflammatory phenotype of patient-derived tendon tear cells, regulating markers of tendon inflammation, including podoplanin, CD90, phosphorylated signal transducer and activator of transcription 1, and IL-6. LXB4 and RvE1 counterregulate inflammatory processes in tendon stromal cells, supporting the role of these molecules as potential therapeutics to resolve tendon inflammation.

Topics: Aged; Anti-Inflammatory Agents; Cells, Cultured; Eicosapentaenoic Acid; Female; Humans; Inflammation; Inflammation Mediators; Lacerations; Lipoxins; Male; Middle Aged; Shoulder; Shoulder Injuries; Shoulder Joint; Stromal Cells; Tendon Injuries; Tendons

This commentary highlights the article by Dakin et al that demonstrates critical roles of bioactive lipids in the resolution of inflammation in shoulder tendon tears.

Topics: Eicosapentaenoic Acid; Humans; Inflammation; Lipids; Lipoxins; Rotator Cuff Injuries; Shoulder; Stromal Cells; Tendon Injuries; Tendons

Severe inflammatory disorders such as sepsis are a major cause of morbidity and mortality worldwide. Mitochondrial dysfunction is regarded as a key feature involved in inflammation pathogenesis. In the present study, we investigated the impact of the omega-3 fatty acid-derived lipid mediator Resolvin E1 (RvE1) on mitochondrial function in experimental pulmonary inflammation. RvE1 was found to exert anti-inflammatory properties in human alveolar epithelial cells during severe inflammation. RvE1 is capable of restoring inflammation-induced mitochondrial dysfunction and the impaired imbalance of mitochondrial fission and fusion. Experimental inhibition of mitochondrial fission with Mdivi-1 in our model is associated with a significantly reduced inflammatory response and improved mitochondrial function. These findings suggest a novel functional mechanism for the beneficial effects of RvE1 in experimental pulmonary inflammatory reactions.

Topics: A549 Cells; Alveolar Epithelial Cells; Apoptosis; Eicosapentaenoic Acid; Humans; Inflammation; Mitochondria

Dysfunction in the resolution of inflammation may play a key role in Alzheimer's disease (AD). In this study, we found that the levels of specialized pro-resolving lipid mediators (SPMs) in the hippocampus of 5xFAD mice are significantly lower than in non-transgenic littermates. We, therefore, tested the hypothesis that treatment with resolvin E1 (RvE1) and lipoxin A4 (LXA4) alone or in combination will reverse the neuroinflammatory process and decrease Aβ pathology. 5xFAD mice were treated intraperitoneally starting at 1month of age with RvE1 or LXA4 alone or in combination at a dose of 1.5 μg/kg, 3 times a week until 3months of age. We found that treatment with RvE1 or LXA4 alone or in combination increased the concentration of RvE1, LXA4, and RvD2 in the hippocampus as measured by ELISA. Combination treatment of RvE1 and LXA4 had a more potent effect on the activation of microglia and astrocytes than either treatment alone, measured by immunohistochemistry with Iba1 and GFAP antibodies, respectively. The concentrations of Aβ40 and Aβ42 were measured by ELISA and the percentage of Aβ plaques were analyzed by immunohistochemistry. All treatments single and in combination, decreased the measures of Aβ pathology and restored the homeostasis reversing the inflammatory process for inflammatory cytokines and chemokines (GM-CSF, IFN-γ, IL-1β, IL-6, IL-10, TNF-α, MCP-1, MIP-1α, MIP-1β, and RANTES) as measured by multiplex immunoassay. Overall, the study showed that the levels of SPMs in the hippocampus of 5xFAD mice were significantly lower than in wild-type mice; that treatment with RvE1 and LXA4 restored the level of these compounds, reversed the inflammatory process, and decreased the neuroinflammation associated with Aβ pathology in 5xFAD mice.

Topics: Alzheimer Disease; Animals; Anti-Inflammatory Agents, Non-Steroidal; Disease Models, Animal; Drug Therapy, Combination; Eicosapentaenoic Acid; Female; Hippocampus; Inflammation; Lipoxins; Mice; Mice, Transgenic

While the treatment of inflammatory disorders is generally based on inhibiting factors that drive onset of inflammation, these therapies can compromise healing (NSAIDs) or dampen immunity against infections (biologics). In search of new antiinflammatories, efforts have focused on harnessing endogenous pathways that drive resolution of inflammation for therapeutic gain. Identification of specialized pro-resolving mediators (SPMs) (lipoxins, resolvins, protectins, maresins) as effector molecules of resolution has shown promise in this regard. However, their action on inflammatory resolution in humans is unknown. Here, we demonstrate using a model of UV-killed Escherichia coli-triggered skin inflammation that SPMs are biosynthesized at the local site at the start of resolution, coinciding with the expression of receptors that transduce their actions. These include receptors for lipoxin A4 (ALX/FPR2), resolvin E1 (ChemR23), resolvin D2 (GPR18), and resolvin D1 (GPR32) that were differentially expressed on the endothelium and infiltrating leukocytes. Administering SPMs into the inflamed site 4 hours after bacterial injection caused a reduction in PMN numbers over the ensuing 6 hours, the phase of active resolution in this model. These results indicate that in humans, the appearance of SPMs and their receptors is associated with the beginning of inflammatory resolution and that their therapeutic supplementation enhanced the resolution response.

Topics: Adaptor Proteins, Signal Transducing; Adolescent; Adult; Anti-Inflammatory Agents; Blister; Chemokines; Cytokines; Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Escherichia coli; Humans; Inflammation; Leukocytes; Lipoxins; Male; Middle Aged; Neutrophils; Receptors, Chemokine; Receptors, Formyl Peptide; Receptors, G-Protein-Coupled; Receptors, Lipoxin; Skin; Volunteers; Young Adult

Topics: Animals; Cells, Cultured; Eicosapentaenoic Acid; Inflammation; Inflammation Mediators; Lipopolysaccharides; Mice; Muscle Fibers, Skeletal; Muscle, Skeletal; Muscular Atrophy

Mechanical insults, such as stent implantation, can induce endothelial injury, vascular inflammation, and ultimately lead to vascular neointimal hyperplasia. Resolvin E1 (RvE1), derived from the ω3 fatty acid eicosapentaenoic acid, can facilitate the resolution of inflammation in many settings. We therefore aimed to determine if there was a role for RvE1 in preventing neointimal formation after arterial injury and to understand the underlying mechanisms. Vascular inflammation and neointimal hyperplasia were induced by wire injury in the femoral arteries of mice. Administration of exogenous RvE1 and endogenously generated RvE1 via dietary supplementation with eicosapentaenoic acid and aspirin markedly reduced vascular neointima formation in this model. Mechanistically, RvE1 was found to inhibit vascular neutrophil infiltration, promote macrophage polarization toward an M2-like phenotype, suppress T-cell trafficking by reducing RANTES secretion from vascular smooth muscle cells, and inhibit vascular smooth muscle cell migration. In summary, RvE1 demonstrated a protective role against vascular inflammation and remodeling in response to mechanical injury, suggesting that it may serve as an adjuvant therapeutic agent for percutaneous coronary interventions, such as stent implantation.-Liu, G., Gong, Y., Zhang, R., Piao, L., Li, X., Liu, Q., Yan, S., Shen, Y., Guo, S., Zhu, M., Yin, H., Funk, C. D., Zhang, J., Yu, Y. Resolvin E1 attenuates injury-induced vascular neointimal formation by inhibition of inflammatory responses and vascular smooth muscle cell migration.

Topics: Animals; Cell Movement; Disease Models, Animal; Eicosapentaenoic Acid; Femoral Artery; Inflammation; Male; Mice; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Neointima

Inflammatory disorders such as sepsis are a major cause of morbidity and mortality. Mitochondrial dysfunction is considered a key factor in the pathogenesis of severe inflammation. In the present study, we aimed to investigate the impact of arachidonic acid, omega-3 (n-3) fatty acids, and n-3-derived lipid mediators 18R-HEPE and resolvin (Rv) E1 on mitochondrial function in experimental inflammation. The results revealed that, in contrast to n-6 and n-3 fatty acids, both 18R-HEPE and RvE1 possess anti-inflammatory and anti-apoptotic properties. Both mediators are able to restore inflammation-induced mitochondrial dysfunction, which is characterized by a decrease in mitochondrial respiration and membrane potential, as well as an imbalance of mitochondrial fission and fusion. Furthermore, inhibition of mitochondrial fission by Mdivi-1 and Dynasore reduces levels of the pro-inflammatory cytokines IL-6 and IL-8. These results suggest a novel functional mechanism for the beneficial effects of RvE1 in inflammatory reactions.

Topics: Anti-Inflammatory Agents; Arachidonic Acid; Cell Respiration; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Interleukin-6; Interleukin-8; Leukocytes, Mononuclear; Membrane Potential, Mitochondrial; Mitochondria; Mitochondrial Dynamics; Models, Biological; Primary Cell Culture; Reactive Oxygen Species; Tumor Necrosis Factor-alpha

Topics: Animals; Bone and Bones; Bone Regeneration; Cell Differentiation; Disease Models, Animal; Eicosapentaenoic Acid; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Mice; Osteoblasts; Osteoclasts; Osteogenesis; Osteolysis; Osteoprotegerin; RANK Ligand; Signal Transduction; Tumor Necrosis Factor-alpha

E-series resolvins are biosynthesized from eicosapentaenoic acid during the resolution phase of acute inflammation and enhance inflammation resolution. However, the role of E-series resolvins in inflammation resolution is not yet known. Herein, we show that in human polymorphonuclear neutrophils (PMNs), resolvin E1 (RvE1) selectively enhances reactive oxygen species (ROS) generation induced by N-formylmethionyl-leucyl-phenylalanine. The RvE1-mediated enhancement is eliminated by a pan-antagonist of leukotriene B4 (LTB4) receptors, LY255283, or an NADPH oxidase inhibitor, diphenyleneiodonium. Thus, RvE1 enhances NADPH oxidase-mediated ROS generation via LTB4 receptors. Unlike RvE1, resolvins E2 and E3 do not show such activation of PMNs. Our findings suggest that RvE1 contributes to regulation of ROS generation, in accordance with the inflammatory state of the host.

Topics: Eicosapentaenoic Acid; Fatty Acids, Unsaturated; Humans; Inflammation; N-Formylmethionine Leucyl-Phenylalanine; NADPH Oxidases; Neutrophils; Onium Compounds; Reactive Oxygen Species; Receptors, Leukotriene B4; Tetrazoles

The potential of omega-3 poly-unsaturated fatty acids (PUFAs) as a therapeutic target for psoriasis, a chronic inflammatory skin disease of IL-23/IL-17 axis, is a long-disputed question, since various epidemiological studies have suggested the association between high-intake of omega-3 PUFAs and the reduced frequency and severity of psoriasis. However, their actual significance and the molecular mechanisms remain largely unknown. To address these issues, we focused on resolvin E1 (RvE1), an omega-3 PUFAs-derived metabolite, and examined its effects on psoriatic dermatitis, using an imiquimod-induced mouse psoriasis model. RvE1 potently suppressed the inflammatory cell infiltration and epidermal hyperplasia in the psoriatic skin. RvE1 decreased the mRNA expression of IL-23 in the skin. Consistently, RvE1 inhibited IL-23 production by dendritic cells (DCs) in vitro. Furthermore, RvE1 exerted inhibitory effects on migration of cutaneous DCs and γδ T cells, a major IL-17-producing cell population in mouse, both in vivo and in vitro. These suppressive effects of RvE1 were mediated by its antagonistic function on BLT1, a receptor of leukotriene B4, and were also observed in human DCs, Th17 and Tc17 cells. Our results indicate a novel mechanism of omega-3 PUFA-mediated amelioration of psoriasis, and suggest a potential of RvE1 as a therapeutic target for psoriasis.

Topics: Animals; Cell Movement; Dendritic Cells; Dermatitis; Disease Models, Animal; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Humans; Inflammation; Interleukin-17; Leukotriene B4; Mice; Mice, Inbred C57BL; Psoriasis; RNA, Messenger; Skin; Th17 Cells

Unresolved inflammation is key in linking metabolic dysregulation and the immune system in type 2 diabetes. Successful regulation of acute inflammation requires biosynthesis of specialized proresolving lipid mediators, such as E-series resolvin (RvE) 1, and activation of cognate G protein-coupled receptors. RvE1 binds to leukotriene B4 (BLT-1) on neutrophils and to ERV-1/ChemR23 on monocyte/macrophages. We show novel actions of RvE1 and expression patterns of neutrophil receptors in type 2 diabetes. Neutrophils from healthy subjects express functional BLT-1, low levels of minimally functional ERV-1, and inversed coexpression when compared to neutrophils from type 2 diabetes subjects. Stimulation with TNF-α or LPS increased the expression of ERV-1 by healthy and diabetic neutrophils. RvE1 counteracted LPS and TNF-α induction of ERV-1 overexpression and endogenous diabetic overexpression, activating phagocytosis and resolution signals. Functional ERV-1 was determined by phosphorylation of the signaling protein ribosomal S6. Receptor-antagonism experiments revealed that the increase in phosphorylation of ribosomal S6 was mediated by BLT-1 in healthy subject neutrophils and by ERV-1 in diabetes. Metabololipidomics reveal a proinflammatory profile in diabetic serum. Cell phagocytosis is impaired in type 2 diabetes and requires RvE1 for activation. The dose of RvE1 required to activate resolution signals in type 2 diabetic neutrophils was significantly higher than in healthy controls. RvE1 rescues the dysregulation seen on neutrophil receptor profile and, following a therapeutic dosage, activates phagocytosis and resolution signals in type 2 diabetes. These findings reveal the importance of resolution receptors in health, disease, and dysregulation of inflammation in type 2 diabetes.

Topics: Adult; Cells, Cultured; Chromatography, Liquid; Cytochrome Reductases; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Female; Humans; Inflammation; Male; Middle Aged; Neutrophils; Oxidoreductases Acting on Sulfur Group Donors; Phagocytosis; Polymerase Chain Reaction; Receptors, Leukotriene B4; Tandem Mass Spectrometry; Transcriptome

Sustained inflammation in the brain together with microglia activation can lead to neuronal damage. Hence limiting brain inflammation and activation of microglia is a real therapeutic strategy for inflammatory disease. Resolvin D1 (RvD1) and resolvin E1 (RvE1) derived from n-3 long chain polyunsaturated fatty acids are promising therapeutic compounds since they actively turn off the systemic inflammatory response. We thus evaluated the anti-inflammatory activities of RvD1 and RvE1 in microglia cells in vitro. BV2 cells were pre-incubated with RvD1 or RvE1 before lipopolysaccharide (LPS) treatment. RvD1 and RvE1 both decreased LPS-induced proinflammatory cytokines (TNF-α, IL-6 and IL-1β) gene expression, suggesting their proresolutive activity in microglia. However, the mechanisms involved are distinct as RvE1 regulates NFκB signaling pathway and RvD1 regulates miRNAs expression. Overall, our findings support that pro-resolving lipids are involved in the resolution of brain inflammation and can be considered as promising therapeutic agents for brain inflammation.

Topics: Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Inflammation; Interleukin-6; Mice; Microglia; MicroRNAs; Tumor Necrosis Factor-alpha

Besides LDL-cholesterol, local vascular inflammation plays a key role in atherogenesis. Efficient therapies to treat the inflammatory component of the disease have not been established. The discovery of specialized inflammation-resolving mediators, such as resolvins may provide new opportunities for treatment. This study examines whether the ω-3 fatty acid eicosapentaenoic acid-derived resolvin E1 (RvE1), can reduce atherosclerosis, when administered alone or in combination with a cholesterol-lowering statin.. ApoE*3Leiden mice were fed a hypercholesterolemic diet for 9 weeks and subsequently treated with RvE1-low (1 mg/kg/day), RvE1-high (5 mg/kg/day), atorvastatin (1.5 mg/kg/day) or the combination of atorvastatin and RvE1-low for the following 16 weeks.. RvE1-low and RvE1-high reduced atherosclerotic lesion size to the same extent (-35%; p < 0.05), attenuated the formation of severe lesions, also seen as a proportional increase in the presence of mild lesions, but did not alter plasma cholesterol levels. Cholesterol-lowering atorvastatin reduced atherosclerosis (-27%, p < 0.05), and the combination of RvE1 and atorvastatin further attenuated lesion size (-51%, p < 0.01) and increased the content of mild lesions. RvE1 did not affect plasma SAA, E-selectin, VCAM-1 or MCP-1 but did reduce plasma EPHX4 and down-regulated the local expression of pro-atherogenic genes in the aortae, (e.g. Cd74, Cd44, Ccl2, Ccr5 and Adam17) and significantly inactivated IFN-γ (p < 0.001) and TNF-α (p < 0.001) signalling pathways.. RvE1 attenuates atherogenesis both alone and on top of a statin. The local effects of RvE1 are demonstrated by the modulated aortic expression of genes involved in inflammatory and immune responses, without altering plasma cholesterol or circulating SAA.

Topics: Animals; Aorta; Atherosclerosis; Atorvastatin; Cholesterol; Cholesterol, LDL; E-Selectin; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Female; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Inflammation; Lipids; Mice; Mice, Knockout, ApoE; Oligonucleotide Array Sequence Analysis; Serum Amyloid A Protein; Treatment Outcome; Vascular Cell Adhesion Molecule-1

Periodontitis is a biofilm-induced inflammatory disease characterized by dysbiosis of the commensal periodontal microbiota. It is unclear how natural regulation of inflammation affects the periodontal biofilm. Promoters of active resolution of inflammation, including resolvin E1 (RvE1), effectively treat inflammatory periodontitis in animal models. The goals of this study were 1) to compare periodontal tissue gene expression in different clinical conditions, 2) to determine the impact of local inflammation on the composition of subgingival bacteria, and 3) to understand how inflammation impacts these changes. Two clinically relevant experiments were performed in rats: prevention and treatment of ligature-induced periodontitis with RvE1 topical treatment. The gingival transcriptome was evaluated by RNA sequencing of mRNA. The composition of the subgingival microbiota was characterized by 16S rDNA sequencing. Periodontitis was assessed by bone morphometric measurements and histomorphometry of block sections. H&E and tartrate-resistant acid phosphatase staining were used to characterize and quantify inflammatory changes. RvE1 treatment prevented bone loss in ligature-induced periodontitis. Osteoclast density and inflammatory cell infiltration in the RvE1 groups were lower than those in the placebo group. RvE1 treatment reduced expression of inflammation-related genes, returning the expression profile to one more similar to health. Treatment of established periodontitis with RvE1 reversed bone loss, reversed inflammatory gene expression, and reduced osteoclast density. Assessment of the rat subgingival microbiota after RvE1 treatment revealed marked changes in both prevention and treatment experiments. The data suggest that modulation of local inflammation has a major role in shaping the composition of the subgingival microbiota.

Topics: Animals; Disease Models, Animal; Dysbiosis; Eicosapentaenoic Acid; Inflammation; Male; Periodontitis; Rats; Rats, Wistar

Diabetic complications involve inflammation-mediated microvascular and macrovascular damage, disruption of lipid metabolism, glycosylation of proteins, and abnormalities of neutrophil-mediated events. Resolution of inflamed tissues to health and homeostasis is an active process mediated by endogenous lipid agonists, including lipoxins and resolvins. This proresolution system appears to be compromised in type 2 diabetes (T2D). The goal of this study was to investigate unresolved inflammation in T2D. Wild-type (WT) and genetically engineered mice, including T2D mice (db/db), transgenic mice overexpressing the human resolvin E1 (RvE1) receptor (ERV1), and a newly bred strain of db/ERV1 mice, were used to determine the impact of RvE1 on the phagocytosis of Porphyromonas gingivalis in T2D. Neutrophils were isolated and incubated with fluorescein isothiocyanate-labeled P. gingivalis, and phagocytosis was measured in a fluorochrome-based assay by flow cytometry. Mitogen-activated protein kinase (MAPK) (p42 and p44) and Akt (Thr308 and Ser473) phosphorylation was analyzed by Western blotting. The mouse dorsal air pouch model was used to evaluate the in vivo impact of RvE1. Results revealed that RvE1 increased the neutrophil phagocytosis of P. gingivalis in WT animals but had no impact in db/db animals. In ERV1-transgenic and ERV1-transgenic diabetic mice, phagocytosis was significantly increased. RvE1 decreased Akt and MAPK phosphorylation in the transgenic animals. In vivo dorsal air pouch studies revealed that RvE1 decreases neutrophil influx into the pouch and increases neutrophil phagocytosis of P. gingivalis in the transgenic animals; cutaneous fat deposition was reduced, as was macrophage infiltration. The results suggest that RvE1 rescues impaired neutrophil phagocytosis in obese T2D mice overexpressing ERV1.

Topics: Animals; Bacteroidaceae Infections; Blood Glucose; Diabetes Complications; Diabetes Mellitus, Type 2; Eicosapentaenoic Acid; Flow Cytometry; Glycosylation; Inflammation; Lipid Metabolism; Male; Mice; Mice, Obese; Mice, Transgenic; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Neutrophils; Obesity; Phagocytosis; Phosphorylation; Porphyromonas gingivalis

Traumatic brain injury (TBI) is induced by mechanical forces which initiate a cascade of secondary injury processes, including inflammation. Therapies which resolve the inflammatory response may promote neural repair without exacerbating the primary injury. Specific derivatives of omega-3 fatty acids loosely grouped as specialized pro-resolving lipid mediators (SPMs) and termed resolvins promote the active resolution of inflammation. In the current study, we investigate the effect of two resolvin molecules, RvE1 and AT-RvD1, on post-traumatic sleep and functional outcome following diffuse TBI through modulation of the inflammatory response. Adult, male C57BL/6 mice were injured using a midline fluid percussion injury (mFPI) model (6-10min righting reflex time for brain-injured mice). Experimental groups included mFPI administered RvE1 (100ng daily), AT-RvD1 (100ng daily), or vehicle (sterile saline) and counterbalanced with uninjured sham mice. Resolvins or saline were administered daily for seven consecutive days beginning 3days prior to TBI to evaluate proof-of-principle to improve outcome. Immediately following diffuse TBI, post-traumatic sleep was recorded for 24h post-injury. For days 1-7 post-injury, motor outcome was assessed by rotarod. Cognitive function was measured at 6days post-injury using novel object recognition (NOR). At 7days post-injury, microglial activation was quantified using immunohistochemistry for Iba-1. In the diffuse brain-injured mouse, AT-RvD1 treatment, but not RvE1, mitigated motor and cognitive deficits. RvE1 treatment significantly increased post-traumatic sleep in brain-injured mice compared to all other groups. RvE1 treated mice displayed a higher proportion of ramified microglia and lower proportion of activated rod microglia in the cortex compared to saline or AT-RvD1 treated brain-injured mice. Thus, RvE1 treatment modulated post-traumatic sleep and the inflammatory response to TBI, albeit independently of improvement in motor and cognitive outcome as seen in AT-RvD1-treated mice. This suggests AT-RvD1 may impart functional benefit through mechanisms other than resolution of inflammation alone.

Topics: Animals; Brain Injuries; Cognition; Docosahexaenoic Acids; Eicosapentaenoic Acid; Inflammation; Male; Memory; Mice; Mice, Inbred C57BL; Microglia; Motor Activity; Sleep

Epidemiological and recent clinical studies implicate periodontitis as an independent risk factor for cardiovascular disease. Previously, we demonstrated that rabbits with experimental periodontitis and cholesterol diet exhibit more aortic plaque compared with diet alone. We also showed that a proresolution mediator, Resolvin E1 (RvE1), reverses the experimental periodontitis. Here, we determined whether oral/topical application of RvE1 attenuates aortic atherosclerosis induced by both diet and periodontal inflammation.. Thirty-nine rabbits on a 13-week regimen of 0.5% cholesterol diet were included. Periodontitis was induced by Porphyromonas gingivalis in 24 rabbits and 15 rabbits were placed in no-periodontitis groups. Interventions were no-treatment, vehicle, and RvE1 treatment (4 μg/site or 0.4 μg/site) topically applied 3× per week. At 13 weeks, both periodontitis and atherosclerosis were quantified. Atherosclerotic plaques were assessed by Sudan IV staining, histology, and ex vivo MRI. Serum levels of C-reactive protein were evaluated as a measure of systemic inflammation. RvE1, used as an oral/topical agent, significantly diminished atherogenesis and prevented periodontitis (P<0.05). In the absence of periodontal inflammation, oral/topical application of RvE1 resulted in significantly less arterial plaque, a lower intima/media ratio, and decreased inflammatory cell infiltration compared with no-treatment (P<0.001). Local oral RvE1 application significantly reduced systemic levels of C-reactive protein (P<0.05).. The results suggest that oral/topical RvE1 attenuates enhanced atherogenesis induced by periodontitis and prevents vascular inflammation and atherogenesis in the absence of periodontitis. The inhibition of vascular inflammation with endogenous mediators of resolution of inflammation provides a novel approach in the prevention of atherogenic events.

Topics: Administration, Topical; Animals; Atherosclerosis; Biopsy, Needle; C-Reactive Protein; Diet, Atherogenic; Disease Models, Animal; Eicosapentaenoic Acid; Immunohistochemistry; Inflammation; Male; Periodontitis; Rabbits; Random Allocation; Reference Values; Risk Assessment; Treatment Outcome

Topics: Eicosapentaenoic Acid; Humans; Inflammation; Myocardial Infarction; Periodontitis

Endogenous mediators, such as RvE1 (resolvin E1), promote resolution of an inflammatory response and have potential as novel therapeutic agents. In the present study, we investigated the activity of RvE1 in a model of an acute exacerbation of chronic allergic asthma in mice. Animals sensitized to OVA (ovalbumin) received controlled low-level challenge with aerosolized antigen for 4 weeks, followed by a single moderate-level challenge to simulate an allergen-induced exacerbation of asthmatic inflammation. Induction of an exacerbation was associated with rapid recruitment of neutrophils, lymphocytes and eosinophils, together with increased levels of Th2 and pro-inflammatory cytokines. When administered before the final moderate-level challenge, RvE1 had only a modest effect on airway inflammation. To assess its effects when administered after induction of an exacerbation, we first characterized the cellular and molecular events associated with spontaneous resolution of airway inflammation over the following 96 h. Subsequently, we showed that administration of RvE1 at 2 and 8 h after the final challenge accelerated this process significantly. Specifically, RvE1 promoted a decline in the number of inflammatory cells, concentration of cytokines in lavage fluid and expression of mRNA for cytokines by macrophages, confirming its pro-resolution activity. In vitro, RvE1 had no apparent effect on lymphocytes, but suppressed significantly cytokine production by pulmonary macrophages, with evidence of down-regulation of the nuclear translocation of NF-κB (nuclear factor κB) p65 in these cells. The present study provides novel evidence that RvE1 can facilitate resolution of airway inflammation in a clinically relevant model of an acute exacerbation of asthma, possibly via its effects on activated pulmonary macrophages.

Topics: Active Transport, Cell Nucleus; Animals; Asthma; Bronchial Hyperreactivity; Bronchoalveolar Lavage Fluid; Cell Line; Cytokines; Disease Models, Animal; Eicosapentaenoic Acid; Female; Hypersensitivity; Immunohistochemistry; Inflammation; Leukocytes; Macrophages; Mice; Mice, Inbred BALB C; NF-kappa B; Ovalbumin; RNA, Messenger; Time Factors

The fatty acid mixture of human milk is ideal for the newborn but little is known about its composition in the first few weeks of lactation. Of special interest are the levels of long-chain PUFAs (LCPUFAs), since these are essential for the newborn's development. Additionally, the LCPUFAs arachidonic acid (AA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are precursors for lipid mediators which regulate inflammation.. We determined the composition of 94 human milk samples from 30 mothers over the first month of lactation for fatty acids using GC-MS and quantified lipid mediators using HPLC-MS/MS.. Over the four weeks period, DHA levels decreased, while levels of γC18:3 and αC18:3 steadily increased. Intriguingly, we found high concentrations of lipid mediators and their hydroxy fatty acid precursors in human milk, including pro-inflammatory leukotriene B4 (LTB4) and anti-inflammatory and pro-resolving lipoxin A4 (LXA4), resolvin D1 (RvD1) and resolvin E1 (RvE1). Lipid mediator levels were stable with the exception of two direct precursors.. Elevated levels of DHA right after birth might represent higher requirements of the newborn and the high content of anti-inflammatory and pro-resolving lipid mediators and their precursors may indicate their role in neonatal immunity and may be one of the reasons for the advantage of human milk over infant formula.

Topics: Docosahexaenoic Acids; Eicosanoids; Eicosapentaenoic Acid; Female; Humans; Infant; Infant, Newborn; Inflammation; Lactation; Lipid Metabolism; Lipoxins; Milk, Human; United States

New classes of lipids such as lipoxins, resolvins, protectins and maresin are found to promote the resolution of inflammation. The resolving actions of these endogenous lipids are mediated by membrane receptors such as lipoxin A4 receptor/formyl peptide receptor 2 (ALX/FPR2) and cysteinyl leukotriene receptor 1 (CysLT1). Further, there exists G protein-coupled receptor 32 (GPR32), chemokine receptor-like (CMLKLR), LTB4 receptor 1 (BLT1) and unidentified high-affinity surface binding receptors in human polymorphonuclear leukocytes (PMN). In particular, RX-10001 (resolvin E1) and RX-10004 (synthetic analog of resolvin, phase II) are being studied clinically in many inflammatory diseases including dry eye, retinal disease, asthma, inflammatory bowel diseases, rheumatic arthritis and cardiovascular diseases by Resolvyx Pharmaceuticals. These novel lipid classes of inflammation resolving mediators might offers new opportunities for candidates of drugs modulating chronic inflammatory diseases. Here, the progress of resolvins as new drug candidates is introduced and research on the resolution phase of inflammation is emphasized.

Topics: Animals; Drugs, Investigational; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Lipids; Receptors, Cytoplasmic and Nuclear

Immune responses are pathologically sustained in several common diseases, including asthma. To determine endogenous proresolving mechanisms for adaptive immune responses, we used a murine model of self-limited allergic airway inflammation. After cessation of allergen exposure, eosinophils and T cells were cleared concomitant with the appearance of increased numbers of NK cells in the lung and mediastinal lymph nodes. The mediastinal lymph node NK cells were activated, expressing CD27, CD11b, CD69, CD107a, and IFN-γ. NK cell depletion disrupted the endogenous resolution program, leading to delayed clearance of airway eosinophils and Ag-specific CD4(+) T cells. NK cell trafficking to inflamed tissues for resolution was dependent upon CXCR3 and CD62L. During resolution, eosinophils and Ag-specific CD4(+) T cells expressed NKG2D ligands, and a blocking Ab for the NKG2D receptor delayed clearance of these leukocytes. Of interest, NK cells expressed CMKLR1, a receptor for the proresolving mediator resolvin E1, and depletion of NK cells decreased resolvin E1-mediated resolution of allergic inflammation. Resolvin E1 regulated NK cell migration in vivo and NK cell cytotoxicity in vitro. Together, these findings indicate new functions in catabasis for NK cells that can also serve as targets for proresolving mediators in the resolution of adaptive immunity.

Topics: Adaptive Immunity; Adoptive Transfer; Animals; Bronchoalveolar Lavage Fluid; CD11b Antigen; CD4-Positive T-Lymphocytes; Eicosapentaenoic Acid; Eosinophils; Flow Cytometry; Inflammation; Killer Cells, Natural; Lung; Lymph Nodes; Mice; Mice, Inbred BALB C; Respiratory Hypersensitivity; Respiratory Mucosa; Time Factors; Tumor Necrosis Factor Receptor Superfamily, Member 7

Inflammation when unchecked is associated with many prevalent disorders such as the classic inflammatory diseases arthritis and periodontal disease, as well as the more recent additions that include diabetes and cardiovascular maladies. Hence mechanisms to curtail the inflammatory response and promote catabasis are of immense interest. In recent years, evidence has prompted a paradigm shift whereby the resolution of acute inflammation is a biochemically active process regulated in part by endogenous PUFA (polyunsaturated fatty acid)-derived autacoids. Among these are a novel genus of SPMs (specialized proresolving mediators) that comprise novel families of mediators including lipoxins, resolvins, protectins and maresins. SPMs have distinct structures and act via specific G-protein seven transmembrane receptors that signal intracellular events on selective cellular targets activating proresolving programmes while countering pro-inflammatory signals. An appreciation of these endogenous pathways and mediators that control timely resolution opened a new terrain for therapeutic approaches targeted at stimulating resolution of local inflammation. In the present review, we provide an overview of the biosynthesis and actions of resolvin E1, underscoring its protective role in vascular systems and regulating platelet responses. We also give an overview of newly described resolution circuitry whereby resolvins govern miRNAs (microRNAs), and transcription factors that counter-regulate pro-inflammatory chemokines, cytokines and lipid mediators.

Topics: Animals; Autacoids; Blood Platelets; Docosahexaenoic Acids; Eicosapentaenoic Acid; Homeostasis; Humans; Inflammation; Inflammation Mediators; Lipoxins; Macrophages; Mice; MicroRNAs; Rats

Inflammatory pain such as arthritic pain is typically treated with opioids and cyclo-oxygenase-2 inhibitors with well known side effects. Transient receptor potential subtype vanilloid 1 (TRPV1) and TRP ankyryn 1 (TRPA1) contribute importantly to the genesis of inflammatory pain via both peripheral mechanisms (peripheral sensitization) and spinal cord mechanisms (central sensitization). Although these TRP channels have been intensively studied, little is known about their endogenous inhibitors. Recent studies have demonstrated that the endogenous lipid mediators resolvins (RvE1 and RvD1), derived from ω-3 unsaturated fatty acids, are potent inhibitors for inflammatory pain, without noticeable side effects. However, the molecular mechanisms underlying resolvins' distinct analgesic actions in mice are unclear. RvD2 is a novel family member of resolvins. Here we report that RvD2 is a remarkably potent inhibitor of TRPV1 (IC(50) = 0.1 nm) and TRPA1 (IC(50) = 2 nm) in primary sensory neurons, whereas RvE1 and RvD1 selectively inhibited TRPV1 (IC(50) = 1 nm) and TRPA1 (IC(50) = 9 nm), respectively. Accordingly, RvD2, RvE1, and RvD1 differentially regulated TRPV1 and TRPA1 agonist-elicited acute pain and spinal cord synaptic plasticity [spontaneous EPSC (sEPSC) frequency increase]. RvD2 also abolished inflammation-induced sEPSC increases (frequency and amplitude), without affecting basal synaptic transmission. Intrathecal administration of RvD2 at very low doses (0.01-1 ng) prevented formalin-induced spontaneous pain. Intrathecal RvD2 also reversed adjuvant-induced inflammatory pain without altering baseline pain and motor function. Finally, intrathecal RvD2 reversed C-fiber stimulation-evoked long-term potentiation in the spinal cord. Our findings suggest distinct roles of resolvins in regulating TRP channels and identify RvD2 as a potent endogenous inhibitor for TRPV1/TRPA1 and inflammatory pain.

Topics: Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Ganglia, Spinal; Inflammation; Male; Mice; Neuronal Plasticity; Neurons; Pain; Spinal Cord; TRPV Cation Channels

Resolvin E1 (RvE1), an endogenous lipid mediator derived from eicosapentaenoic acid, has been identified in local inflammation during the healing stage. RvE1 reduces inflammation in several types of animal models including peritonitis and retinopathy and blocks human neutrophil transendothelial cell migration. The RvE1 receptor ChemR23 is expressed on myeloid cells such as macrophages and dendritic cells. The aim of this study was to determine whether RvE1 regulates colonic inflammation when the innate immune response of macrophages plays a key role in pathogenesis and tissue damage.. The RvE1 receptor ChemR23 was expressed in mouse peritoneal macrophages as defined by flow cytometry. Peritoneal macrophages were pretreated with RvE1, followed by lipopolysaccharide stimulation, whereupon transcriptional levels of proinflammatory cytokines were analyzed.. RvE1 treatment led to inhibition of proinflammatory cytokines including TNF-alpha and IL-12p40. In HEK293 cells, pretreatment with RvE1 inhibited TNF-alpha-induced nuclear translocation of NF-kappaB in a ChemR23-dependent manner. These results suggested that RvE1 could regulate proinflammatory responses of macrophages expressing ChemR23. Therefore, we investigated the beneficial effects of RvE1 in dextran sulfate sodium-induced colitis. RvE1 treatment led to amelioration of colonic inflammation.. These results indicate that RvE1 suppresses proinflammatory responses of macrophages. RvE1 and its receptor may therefore be useful as therapeutic targets in the treatment of human inflammatory bowel disease and other inflammatory disorders.

Topics: Animals; Cell Nucleus; Cells, Cultured; Colitis; Dextran Sulfate; Eicosapentaenoic Acid; Female; Flow Cytometry; Humans; Immunoenzyme Techniques; Inflammation; Inflammation Mediators; Kidney; Macrophages, Peritoneal; Mice; Mice, Inbred C57BL; NF-kappa B; Protein Transport; Receptors, Chemokine; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger

Resolvins are endogenous lipid mediators that actively regulate the resolution of acute inflammation. Resolvin E1 (RvE1; (5S,12R,18R)-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is an endogenous anti-inflammatory and pro-resolving mediator derived from eicosapentaenoic acid that regulates leukocyte migration and enhances macrophage phagocytosis of apoptotic neutrophils to resolve inflammation. In the inflammatory milieu, RvE1 mediates counter-regulatory actions initiated via specific G protein-coupled receptors. Here, we have identified RvE1-specific signaling pathways initiated by the RvE1 receptor ChemR23. RvE1 stimulated phosphorylation of Akt that was both ligand- and receptor-dependent. RvE1 regulated Akt phosphorylation in a time (0-15 min)- and dose-dependent (0.01-100 nm) manner in human ChemR23-transfected Chinese hamster ovary cells. RvE1 stimulated phosphorylation of both Akt and a 30-kDa protein, a downstream target of Akt, identified using a phospho-Akt substrate antibody. The 30-kDa protein was identified as ribosomal protein S6, a translational regulator, and its phosphorylation was inhibited by a phosphatidylinositol 3-kinase (PI3K) inhibitor (wortmannin) and an ERK inhibitor (PD98059) but not by a p38-MAPK inhibitor (SB203580). Ribosomal protein S6 is a downstream target of the PI3K/Akt signaling pathway as well as the Raf/ERK pathway. In ChemR23-expressing differentiated HL60 cells, RvE1 also stimulated the phosphorylation of ribosomal protein S6. In addition, RvE1 enhanced phagocytosis of zymosan A by human macrophages, which are inhibited by PD98059 and rapamycin (mTOR inhibitor). These results indicate that RvE1 initiates direct activation of ChemR23 and signals receptor-dependent phosphorylation. These phosphorylation-signaling pathways identified for RvE1 receptor-ligand interactions underscore the importance of endogenous pro-resolving agonists in resolving acute inflammation.

Topics: Animals; Cell Differentiation; CHO Cells; Cricetinae; Cricetulus; Eicosapentaenoic Acid; Flavonoids; HL-60 Cells; Humans; Inflammation; Lipids; Macrophages; Phagocytosis; Phosphorylation; Receptors, Chemokine; Sirolimus; Zymosan

In clinical islet transplantation, inflammatory responses initiated by the transplanted islets and by the host immune system cause acute and chronic graft loss. The resolution of acute inflammation is an active process mediated by specific signals and mediators such as resolvin E1 (RvE1). We investigated the effect of RvE1 on i) the inflammatory status of human pancreatic islets, ii) islet viability and apoptosis, and iii) the instant blood-mediated inflammatory reaction (IBMIR) IN VITRO.. Pro-inflammatory cytokines and tissue factor (TF) in isolated human islets were determined by real-time RT-qPCR (mRNA levels), CBA and Gyrolab bioaffy (protein levels) after lipopolysaccaride (LPS) stimulation. Islet viability was measured using insulin secretion in a dynamic model, ADP/ATP ratio and total ATP content. Apoptosis was measured using commercial kits after stimulation with proinflammatory cytokines. To assess effect on IBMIR, human islets were mixed with non-anticoagulated, RvE1 or vehicle pretreated ABO-compatible blood in heparin-coated tubing loops.. Treatment of human islets with RvE1 (500 nM) for 24 h reduced LPS-induced increase in mRNA and protein levels of selected pro-inflammatory markers (IL-8, MCP-1, and TF). RvE1 lowered the ADP/ATP ratio, but had no effect on insulin secretion. RvE1 reduced the apoptotic effect of proinflammatory cytokines. Additionally, RvE1 reduced platelet consumption and TAT complex formation during the first 5 min after islet-blood contact.. RvE1 suppresses proinflammatory markers and lowers the ADP/ATP ratio in human islets IN VITRO. RvE1 demonstrates anti-apoptotic effects in a proinflammatory milieu. Additionally, RvE1 has modest dampening effects on IBMIR. We conclude that RvE1 may have potential in clinical islet transplantation.

Topics: Analysis of Variance; Apoptosis; Biomarkers; Cell Survival; Cytokines; Eicosapentaenoic Acid; Humans; Immunoenzyme Techniques; Inflammation; Inflammation Mediators; Insulin; Insulin Secretion; Islets of Langerhans; Organ Culture Techniques; Receptors, Leukotriene B4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Thromboplastin

Inflammatory pain, such as arthritis pain, is a growing health problem. Inflammatory pain is generally treated with opioids and cyclooxygenase (COX) inhibitors, but both are limited by side effects. Recently, resolvins, a unique family of lipid mediators, including RvE1 and RvD1 derived from omega-3 polyunsaturated fatty acid, have shown marked potency in treating disease conditions associated with inflammation. Here we report that peripheral (intraplantar) or spinal (intrathecal) administration of RvE1 or RvD1 in mice potently reduces inflammatory pain behaviors induced by intraplantar injection of formalin, carrageenan or complete Freund's adjuvant (CFA), without affecting basal pain perception. Intrathecal RvE1 injection also inhibits spontaneous pain and heat and mechanical hypersensitivity evoked by intrathecal capsaicin and tumor necrosis factor-alpha (TNF-alpha). RvE1 has anti-inflammatory activity by reducing neutrophil infiltration, paw edema and proinflammatory cytokine expression. RvE1 also abolishes transient receptor potential vanilloid subtype-1 (TRPV1)- and TNF-alpha-induced excitatory postsynaptic current increases and TNF-alpha-evoked N-methyl-D-aspartic acid (NMDA) receptor hyperactivity in spinal dorsal horn neurons via inhibition of the extracellular signal-regulated kinase (ERK) signaling pathway. Thus, we show a previously unknown role for resolvins in normalizing the spinal synaptic plasticity that has been implicated in generating pain hypersensitivity. Given the potency of resolvins and the well-known side effects of opioids and COX inhibitors, resolvins may represent new analgesics for treating inflammatory pain.

Topics: Analgesics; Animals; Docosahexaenoic Acids; Eicosapentaenoic Acid; Inflammation; Injections, Spinal; Male; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mice, Knockout; Pain; Posterior Horn Cells

Topics: Analgesics; Docosahexaenoic Acids; Eicosapentaenoic Acid; Humans; Inflammation; Models, Biological; Molecular Structure; Pain

Resolvin-E1 (RvE1) has been demonstrated to promote inflammatory resolution in numerous disease models. Given the importance of epithelial cells to coordination of mucosal inflammation, we hypothesized that RvE1 elicits an epithelial resolution signature. Initial studies revealed that the RvE1-receptor (ChemR23) is expressed on intestinal epithelial cells (IECs) and that microarray profiling of cells exposed to RvE1 revealed regulation of inflammatory response gene expression. Notably, RvE1 induced intestinal alkaline phosphatase (ALPI) expression and significantly enhanced epithelial ALPI enzyme activity. One role recently attributed to ALPI is the detoxification of bacterial LPS. In our studies, RvE1-exposed epithelia detoxified LPS (assessed by attenuation of NF-kappaB signaling). Furthermore, in epithelial-bacterial interaction assays, we determined that ALPI retarded the growth of Escherichia coli. To define these features in vivo, we used a murine dextran sulfate sodium (DSS) model of colitis. Compared with vehicle controls, administration of RvE1 resulted in significant improvement of disease activity indices (e.g., body weight, colon length) concomitant with increased ALPI expression in the intestinal epithelium. Moreover, inhibition of ALPI activity resulted in increased severity of colitis in DSS-treated animals and partially abrogated the protective influence of RvE1. Together, these data implicate a previously unappreciated role for ALPI in RvE1-mediated inflammatory resolution.

Topics: Alkaline Phosphatase; Animals; Colitis; Eicosapentaenoic Acid; Epithelial Cells; Female; Gene Expression Profiling; Gene Expression Regulation; Inflammation; Intestinal Mucosa; Lipopolysaccharides; Mice; Mice, Inbred C57BL; Receptors, Cell Surface; Transcriptional Activation

Dry eye (DE) is a common ocular surface disease, particularly among women and the elderly, with chronic symptoms of eye irritation and, in severe cases, blurred vision. Several studies have shown that there is an inflammatory component in DE, although the pathogenesis is not thoroughly understood. Resolvin E1 (RvE1; RX-10001) is an endogenous mediator derived from the omega-3 polyunsaturated fatty acid eicosapentaenoic acid and is involved in inflammation resolution and tissue protection. Here we investigated the role of RvE1 in a DE mouse model.. Thirteen- to 14-week-old female BALB/C mice were exposed to desiccating conditions. One week after DE exposure, animals were treated topically with drug or vehicle 4 times per day for an additional week. Controls were nontreated animals placed in a normal environment. Schirmer's test was performed before treatment initiation and at days 2 and 4 after treatment. Density of corneal epithelial cells was analyzed in vivo using the Rostock Cornea Module of the Heidelberg Retina Tomograph (HRT-II). Corneas were processed using Western blot analysis and immunofluorescence examination.. Schirmer's test showed a significant decrease in tear production in DE compared with controls. There was no change at 2 and 4 days after treatment with the vehicle, but a significant increase was observed at 2 and 4 days in the RvE1-treated group. The density of the superficial epithelial cells showed a significant decrease after DE compared with controls, which increased after 7 days of RvE1 treatment. Western blot analysis showed that α-smooth muscle actin and cyclooxygenase-2 (COX-2) expression were strongly upregulated after DE and decreased after 7 days of RvE1 treatment. Immunofluorescence confirmed strong positive staining of α-smooth muscle actin and COX-2 in stroma and/or in epithelia after DE, which decreased with RvE1 treatment. The percentage of infiltrating CD⁴+ T cells and CD11b+ cells decreased after RvE1 treatment when compared with DE.. RvE1 promotes tear production, corneal epithelial integrity, and a decrease in inflammatory inducible COX-2. In the stroma, RvE1 inhibits keratocyte transformation to myofibroblasts and lowers the number of monocytes/macrophages in this DE mouse model. These results suggest that RvE1 and similar resolvin analogs have therapeutic potential in the treatment of DE.

Topics: Actins; Animals; CD11b Antigen; CD4 Antigens; Cornea; Cyclooxygenase 2; Disease Models, Animal; Dry Eye Syndromes; Eicosapentaenoic Acid; Epithelial Cells; Female; Inflammation; Mice; Mice, Inbred BALB C; Myofibroblasts; Tears

Interleukin 23 (IL-23) is integral to the pathogenesis of chronic inflammation. The resolution of acute inflammation is an active process mediated by specific signals and mediators such as resolvin E1 (RvE1). Here we provide evidence that RvE1, in nanogram quantities, promoted the resolution of inflammatory airway responses in part by directly suppressing the production of IL-23 and IL-6 in the lung. Also contributing to the pro-resolution effects of RvE1 treatment were higher concentrations of interferon-gamma in the lungs of RvE1-treated mice. Our findings indicate a pivotal function for IL-23 and IL-6, which promote the survival and differentiation of IL-17-producing T helper cells, in maintaining inflammation and also identify an RvE1-initiated resolution program for allergic airway responses.

Topics: Animals; Asthma; Disease Models, Animal; Eicosapentaenoic Acid; Inflammation; Inflammation Mediators; Interferon-gamma; Interleukin-23; Lipoxins; Lung; Mice

The inflammation-resolving lipid mediator resolvin E1 (RvE1) effectively stops inflammation-induced bone loss in vivo in experimental periodontitis. It was of interest to determine whether RvE1 has direct actions on osteoclast (OC) development and bone resorption.. Primary OC cultures derived from mouse bone marrow were treated with RvE1 and analysed for OC differentiation, cell survival and bone substrate resorption. Receptor binding was measured using radiolabelled RvE1. Nuclear factor (NF)-kappaB activation and Akt phosphorylation were determined with western blotting. Lipid mediator production was assessed with liquid chromatography tandem mass spectrometry.. OC growth and resorption pit formation were markedly decreased in the presence of RvE1. OC differentiation was inhibited by RvE1 as demonstrated by decreased number of multinuclear OC, a delay in the time course of OC development and attenuation of receptor activator of NF-kappaB ligand-induced nuclear translocation of the p50 subunit of NF-kappaB. OC survival and apoptosis were not altered by RvE1. Messenger RNA for both receptors of RvE1, ChemR23 and BLT(1) is expressed in OC cultures. Leukotriene B(4) (LTB(4)) competed with [(3)H]RvE1 binding on OC cell membrane preparations, and the LTB(4) antagonist U75302 prevented RvE1 inhibition of OC growth, indicating that BLT(1) mediates RvE1 actions on OC. Primary OC synthesized the RvE1 precursor 18R-hydroxy-eicosapentaenoic acid and LTB(4). Co-incubation of OC with peripheral blood neutrophils resulted in transcellular RvE1 biosynthesis.. These results indicate that RvE1 inhibits OC growth and bone resorption by interfering with OC differentiation. The bone-sparing actions of RvE1 are in addition to inflammation resolution, a direct action in bone remodelling.

Topics: Animals; Apoptosis; Bone Resorption; Cell Differentiation; Cells, Cultured; Dentin; Eicosapentaenoic Acid; Inflammation; Leukotriene B4; Mice; Osteoclasts; Radioligand Assay

Resolvin E1 (RvE1; 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-eicosapentaenoic acid) is a potent anti-inflammatory and proresolving mediator derived from the omega-3 eicosapentaenoic acid. In this study, we report the RvE1 metabolome, namely, the metabolic products derived from RvE1. RvE1 was converted to several novel products by human polymorphonuclear leukocytes and whole blood as well as in murine inflammatory exudates, spleen, kidney, and liver. The potential activity of each of the newly identified products was directly compared with that of RvE1. The new RvE1 products elucidated included 19-hydroxy-RvE1, 20-carboxy-RvE1, and 10,11-dihydro-RvE1. Metabolomic profiles of RvE1 were species-, tissue-, and cell type-specific. Direct comparisons of the bioactions between isolated RvE1 metabolic products indicated that 10,11-dihydro-RvE1, 18-oxo-RvE1, and 20-carboxy-RvE1 displayed reduced bioactivity in vivo. At concentrations as low as 1 nM, RvE1 enhanced macrophage phagocytosis, a proresolving activity that was reduced by metabolic inactivation. These results document novel metabolic products of RvE1 that impact its actions and that both omega-1 hydroxylation and reduction of conjugated double bonds in RvE1 are new pathways of four main routes of RvE1 metabolism in mammalian tissues. Together, these findings indicate that, during inflammation and its controlled resolution, specific tissues inactivate proresolving signals, i.e., RvE1, to permit the coordinated return to homeostasis. Moreover, the RvE1 metabolome may serve as a biomarker of these processes.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Ascitic Fluid; Eicosapentaenoic Acid; Humans; Inflammation; Inflammation Mediators; Macrophages, Peritoneal; Male; Mice; Mice, Inbred Strains; Neutrophils; Phagocytosis; Signal Transduction

Inflammation governs atherosclerosis and is firmly regulated. Endogenous mechanisms to keep inflammation self-limiting are unclear. In the present article, we propose that RvE1 (resolution E1), an endogenous lipid mediator, inhibits inflammation through "pro-resolution" and counter-modulating immunity in atherosclerosis. The background comes from studies on the potent programming of resolution and immuno-inflammation of RvE1 and its precursor, eicosapentaenoic acid, in treating chronic inflammatory disease with unknown mechanisms. In light of the interaction between RvE1 and leukotrieneB4 (LTB4) and their potential impaired immunity regulation hematostasis, we hypothesize that RvE1 play an anti-atherosclerosis and plaque stabilization role through "pro-resolution" and anti-inflammation which may be realized by blocking LTB4/BLT1 (receptor of LTB4) pathway. Our hypothesis generates potentially clinical viewpoint to systematically look for pro- and anti-inflammation and "pro-resolution" process in atherosclerosis. Furthermore, we suggest that RvE1 might be particularly indicated for the treatment of atherosclerotic diseases and plaque stabilization which might ensure an effective management for patients with coronary artery disease.

Topics: Anti-Inflammatory Agents; Atherosclerosis; Coronary Artery Disease; Eicosapentaenoic Acid; Hemostasis; Humans; Immune System; Inflammation; Leukotriene B4; Lipids; Models, Biological; Models, Theoretical

Migration of neutrophils (PMN) across epithelia is a pathological hallmark of numerous mucosal diseases. Whereas lesions at mucosal surfaces are generally self-limiting, endogenous mechanisms of resolution are incompletely understood. Previous studies revealed that resolvins directly act on PMN to attenuate transendothelial migration, less is known about the influence of resolvins on PMN-epithelial interactions and whether they act on epithelia. We studied the dynamics of resolvin E1 (RvE1) actions on leukocyte transepithelial migration. PMN exposure to RvE1 or chemerin (peptide agonist of ChemR23) reduced transepithelial migration in a concentration-dependent manner. Conversely, activation of epithelial ChemR23 promoted apical clearance of PMN. A nonbiased screen of known PMN ligands expressed on epithelial cells in response to RvE1 revealed selective induction of CD55, an apically expressed antiadhesive molecule. CD55 promoter analysis demonstrated that both RvE1 and chemerin activate the CD55 promoter. Inhibition of CD55 by neutralizing antibody prevented RvE1-dependent augmentation of apical PMN clearance. Taken together these findings implicate a "two-hit" model of inflammatory resolution, whereby activation of the PMN RvE1 receptor attenuates transepithelial migration and subsequent actions on the epithelium promote CD55-dependent clearance of PMN across the epithelial cell surface promoting active inflammatory resolution.

Topics: Animals; CD55 Antigens; Cell Line; Cell Movement; Chemokines; Eicosapentaenoic Acid; Epithelial Cells; Humans; Inflammation; Intercellular Adhesion Molecule-1; Intercellular Signaling Peptides and Proteins; Mucous Membrane; Neutrophils; Promoter Regions, Genetic

Resolvin E1 (RvE1) is a potent proresolving mediator of inflammation derived from omega-3 eicosapentaenoic acid that acts locally to stop leukocyte recruitment and promote resolution. RvE1 displays potent counter-regulatory and tissue-protective actions in vitro and in vivo. Periodontal disease is a local inflammatory disease initiated by bacteria characterized by neutrophil-mediated tissue injury followed by development of a chronic immune lesion. In this study, we report the treatment of established periodontitis using RvE1 as a monotherapy in rabbits compared with structurally related lipids PGE(2) and leukotriene B(4). PGE(2) and leukotriene B(4) each enhanced development of periodontitis and worsened the severity of disease. Promotion of resolution of inflammation as a therapeutic target with RvE1 resulted in complete restoration of the local lesion, and reduction in the systemic inflammatory markers C-reactive protein and IL-1beta. This report is the first to show that resolution of inflammation by a naturally occurring endogenous lipid mediator results in complete regeneration of pathologically lost tissues, including bone.

Topics: Alveolar Bone Loss; Animals; C-Reactive Protein; Chronic Disease; Dinoprostone; Disease Models, Animal; Eicosapentaenoic Acid; Homeostasis; Inflammation; Inflammation Mediators; Interleukin-1beta; Leukotriene B4; Neutrophil Infiltration; Neutrophils; Periodontitis; Rabbits

Periodontitis is a well-appreciated example of leukocyte-mediated bone loss and inflammation that has pathogenic features similar to those observed in other inflammatory diseases such as arthritis. Resolvins are a new family of bioactive products of omega-3 fatty acid transformation circuits initiated by aspirin treatment that counter proinflammatory signals. Because it is now increasingly apparent that local inflammation plays a critical role in many diseases, including cardiovascular disease, atherosclerosis, and asthma, experiments were undertaken to evaluate the actions of the newly described EPA-derived Resolvin E1 (RvE1) in regulation of neutrophil tissue destruction and resolution of inflammation. The actions of an aspirin-triggered lipoxin (LX) analog and RvE1 in a human disease, localized aggressive periodontitis (LAP), were determined. Results indicate that neutrophils from LAP are refractory to anti-inflammatory molecules of the LX series, whereas LAP neutrophils respond to RvE1. In addition, RvE1 specifically binds to human neutrophils at a site that is functionally distinct from the LX receptor. Consistent with these potent actions, topical application of RvE1 in rabbit periodontitis conferred dramatic protection against inflammation induced tissue and bone loss associated with periodontitis.

Topics: Administration, Topical; Alveolar Bone Loss; Animals; Eicosapentaenoic Acid; Humans; Inflammation; Lipoxins; Male; Metronidazole; Neutrophils; Osteoclasts; Periodontitis; Porphyromonas gingivalis; Rabbits; Superoxides

The essential fatty acid eicosapentaenoic acid (EPA) present in fish oils displays beneficial effects in a range of human disorders associated with inflammation including cardiovascular disease. Resolvin E1 (RvE1), a new bioactive oxygenated product of EPA, was identified in human plasma and prepared by total organic synthesis. Results of bioaction and physical matching studies indicate that the complete structure of RvE1 is 5S,12R,18R-trihydroxy-6Z,8E,10E,14Z,16E-EPA. At nanomolar levels, RvE1 dramatically reduced dermal inflammation, peritonitis, dendritic cell (DC) migration, and interleukin (IL) 12 production. We screened receptors and identified one, denoted earlier as ChemR23, that mediates RvE1 signal to attenuate nuclear factor-kappaB. Specific binding of RvE1 to this receptor was confirmed using synthetic [(3)H]-labeled RvE1. Treatment of DCs with small interference RNA specific for ChemR23 sharply reduced RvE1 regulation of IL-12. These results demonstrate novel counterregulatory responses in inflammation initiated via RvE1 receptor activation that provide the first evidence for EPA-derived potent endogenous agonists of antiinflammation.

Topics: Amino Acid Sequence; Animals; Dendritic Cells; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Gene Expression Regulation; Humans; Inflammation; Ligands; Male; Mice; Molecular Sequence Data; Molecular Structure; Phylogeny; Radioligand Assay; Receptors, Chemokine; Sequence Alignment; Signal Transduction; Spleen

The cellular events underlying the resolution of acute inflammation are not known in molecular terms. To identify anti-inflammatory and proresolving circuits, we investigated the temporal and differential changes in self-resolving murine exudates using mass spectrometry-based proteomics and lipidomics. Key resolution components were defined as resolution indices including Psi(max), the maximal neutrophil numbers that are present during the inflammatory response; T(max), the time when Psi(max) occurs; and the resolution interval (R(i)) from T(max) to T(50) when neutrophil numbers reach half Psi(max). The onset of resolution was at approximately 12 h with proteomic analysis showing both haptoglobin and S100A9 levels were maximal and other exudate proteins were dynamically regulated. Eicosanoids and polyunsaturated fatty acids first appeared within 4 h. Interestingly, the docosahexaenoic acid-derived anti-inflammatory lipid mediator 10,17S-docosatriene was generated during the R(i). Administration of aspirin-triggered lipoxin A(4) analog, resolvin E1, or 10,17S-docosatriene each either activated and/or accelerated resolution. For example, aspirin-triggered lipoxin A(4) analog reduced Psi(max), resolvin E1 decreased both Psi(max) and T(max), whereas 10,17S-docosatriene reduced Psi(max), T(max), and shortened R(i). Also, aspirin-triggered lipoxin A(4) analog markedly inhibited proinflammatory cytokines and chemokines at 4 h (20-50% inhibition), whereas resolvin E1 and 10,17S-docosatriene's inhibitory actions were maximal at 12 h (30-80% inhibition). Moreover, aspirin-triggered lipoxin A(4) analog evoked release of the antiphlogistic cytokine TGF-beta. These results characterize the first molecular resolution circuits and their major components activated by specific novel lipid mediators (i.e., resolvin E1 and 10,17S-docosatriene) to promote resolution.

Topics: Animals; Calgranulin B; Eicosanoids; Eicosapentaenoic Acid; Gene Expression Regulation; Haptoglobins; Inflammation; Lipids; Male; Mass Spectrometry; Mice; Mice, Inbred Strains; Neutrophils; Proteins

Topics: Animals; Anti-Inflammatory Agents; Eicosapentaenoic Acid; Fish Oils; Humans; Inflammation