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Nature Communications Nov 2023Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream...
Systemic inflammation has been implicated in the pathobiology of heart failure with preserved ejection fraction (HFpEF). Here, we examine the association of upstream mediators of inflammation as ascertained by fatty-acid derived eicosanoid and eicosanoid-related metabolites with HFpEF status and exercise manifestations of HFpEF. Among 510 participants with chronic dyspnea and preserved LVEF who underwent invasive cardiopulmonary exercise testing, we find that 70 of 890 eicosanoid and related metabolites are associated with HFpEF status, including 17 named and 53 putative eicosanoids (FDR q-value < 0.1). Prostaglandin (15R-PGF2α, 11ß-dhk-PGF2α) and linoleic acid derivatives (12,13 EpOME) are associated with greater odds of HFpEF, while epoxides (8(9)-EpETE), docosanoids (13,14-DiHDPA), and oxylipins (12-OPDA) are associated with lower odds of HFpEF. Among 70 metabolites, 18 are associated with future development of heart failure in the community. Pro- and anti-inflammatory eicosanoid and related metabolites may contribute to the pathogenesis of HFpEF and serve as potential targets for intervention.
Topics: Humans; Heart Failure; Stroke Volume; Dyspnea; Exercise Test; Eicosanoids; Exercise Tolerance
PubMed: 37985769
DOI: 10.1038/s41467-023-43363-3 -
Physiological Research Oct 2019Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated... (Review)
Review
Epoxyeicosatrienoic acids (EETs) are also known as epoxyeicosanoids that have renal and cardiovascular actions. These renal and cardiovascular actions can be regulated by soluble epoxide hydrolase (sEH) that degrades and inactivates EETs. Extensive animal hypertension studies have determined that vascular, epithelial transport, and anti-inflammatory actions of EETs lower blood pressure and decrease renal and cardiovascular disease progression. Human studies have also supported the notion that increasing EET levels in hypertension could be beneficial. Pharmacological and genetic approaches to increase epoxyeicosanoids in several animal models and humans have found improved endothelial vascular function, increased sodium excretion, and decreased inflammation to oppose hypertension and associated renal and cardiovascular complications. These compelling outcomes support the concept that increasing epoxyeicosanoids via sEH inhibitors or EET analogs could be a valuable hypertension treatment.
Topics: Animals; Antihypertensive Agents; Blood Pressure; Eicosanoids; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hypertension; Signal Transduction
PubMed: 31475560
DOI: 10.33549/physiolres.934291 -
The European Respiratory Journal Oct 2023Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with...
BACKGROUND
Eicosanoids are bioactive lipids that regulate systemic inflammation and exert vasoactive effects. Specific eicosanoid metabolites have previously been associated with pulmonary hypertension (PH), yet their role remains incompletely understood.
METHODS
We studied 482 participants with chronic dyspnoea who underwent clinically indicated cardiopulmonary exercise testing (CPET) with invasive haemodynamic monitoring. We performed comprehensive profiling of 888 eicosanoids and eicosanoid-related metabolites using directed non-targeted mass spectrometry, and examined associations with PH (mean pulmonary arterial pressure (mPAP) >20 mmHg), PH subtypes and physiological correlates, including transpulmonary metabolite gradients.
RESULTS
Among 482 participants (mean±sd age 56±16 years, 62% women), 200 had rest PH. We found 48 eicosanoids and eicosanoid-related metabolites that were associated with PH. Specifically, prostaglandin (11β-dhk-PGF2α), linoleic acid (12,13-EpOME) and arachidonic acid derivatives (11,12-DiHETrE) were associated with higher odds of PH (false discovery rate q<0.05 for all). By contrast, epoxide (8(9)-EpETE), α-linolenic acid (13()-HOTrE(γ)) and lipokine derivatives (12,13-DiHOME) were associated with lower odds. Among PH-related eicosanoids, 14 showed differential transpulmonary metabolite gradients, with directionality suggesting that metabolites associated with lower odds of PH also displayed pulmonary artery uptake. In individuals with exercise PH, eicosanoid profiles were intermediate between no PH and rest PH, with six metabolites that differed between rest and exercise PH.
CONCLUSIONS
Our findings highlight the role of specific eicosanoids, including linoleic acid and epoxide derivatives, as potential regulators of inflammation in PH. Of note, physiological correlates, including transpulmonary metabolite gradients, may prioritise future studies focused on eicosanoid-related pathways as important contributors to PH pathogenesis.
Topics: Humans; Female; Adult; Middle Aged; Aged; Male; Hypertension, Pulmonary; Linoleic Acid; Eicosanoids; Inflammation; Epoxy Compounds
PubMed: 37857430
DOI: 10.1183/13993003.00561-2023 -
Nature Reviews. Immunology Aug 2015Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related... (Review)
Review
Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network that is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signalling, similar to cytokine signalling and inflammasome formation, has primarily been viewed as a pro-inflammatory component of the innate immune response; however, recent advances in lipidomics have helped to elucidate unique eicosanoids and related docosanoids with anti-inflammatory and pro-resolution functions. This has advanced our overall understanding of the inflammatory response and its therapeutic implications. The induction of a pro-inflammatory and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed here.
Topics: Animals; Bacterial Infections; Cytochrome P-450 Enzyme System; Cytokines; Eicosanoids; Gene Expression Regulation; Humans; Immunity, Innate; Inflammation; Inflammation Mediators; Lipid Metabolism; Phospholipases; Prostaglandin-Endoperoxide Synthases; Signal Transduction
PubMed: 26139350
DOI: 10.1038/nri3859 -
Biochemical Pharmacology Oct 2022In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports... (Review)
Review
In this review it is attempted to summarize current studies about formation of eicosanoids and other oxylipins in different human macrophages. There are several reports on M1 and M2 cells, also other phenotypes have been described. The eicosanoids formed in the largest amounts are the COX products TxB and PGE. Thus shortlived bioactive TxA is a dominating product both in M1- and in M2-lineages, one exception seems to be M cells. 5-LOX products are produced in both M1 and M2 macrophages, as well as in not fully polarized cells of both lineages. M as well as M2 macrophages produced LTC more readily compared to M1 lineage cells. In M cells LTB is a major eicosanoid, in line with high expression of LTA hydrolase. Recent reports described increased formation of leukotrienes in macrophages subjected to trained immunity with inflammatory transcriptional reprogramming. Also in macrophages derived from monocytes collected from post-COVID-19 patients. 15-LOX-1 is strongly upregulated in CD206 M2 cells (M2a), differentiated in presence of IL-4. These macrophages also express 15-LOX-2. In incubations with pathogenic E. coli as well as other stimuli 15(S)-HETE and 17(S)-HDHA were major oxylipins formed. Also, the SPM precursor 5,15-diHETE and the SPM RvD5 were produced in considerable amounts, while other SPMs were less abundant. In M2 macrophages incubated with E. coli or S. aureus the cytosolic 15-LOX-1 enzyme accumulated to punctuate structures in a Ca dependent manner with a relatively slow time course, leading to formation of mediators from endogenous substrate. Chalcones, flavone-like anti-inflammatory natural products, induced translocation of 15-LOX-1 in M2 cells, with high formation of 15-LOX derived oxylipins.
Topics: Arachidonate 5-Lipoxygenase; Biological Products; COVID-19; Chalcones; Cyclooxygenase 2; Eicosanoids; Escherichia coli; Flavones; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Hydrolases; Hydroxyeicosatetraenoic Acids; Interleukin-4; Leukotrienes; Macrophage Colony-Stimulating Factor; Macrophages; Oxylipins; Prostaglandins E; Scavenger Receptors, Class E; Staphylococcus aureus; Transforming Growth Factor beta
PubMed: 35973581
DOI: 10.1016/j.bcp.2022.115210 -
Trends in Biochemical Sciences Mar 2019Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and... (Review)
Review
Eicosanoids and specialized proresolving mediators (SPMs) regulate leukocyte function and inflammation. They are ideally positioned at the interface of the innate and adaptive immune responses when lymphocytes interact with leukocytes. Receptors for leukotriene B (LTB), prostaglandin E (PGE), and SPMs are expressed on lymphocytes. Evidence points toward an essential role of these lipid mediators (LMs) in direct regulation of lymphocyte functions. SPMs, which include lipoxins, demonstrate comprehensive protective actions with lymphocytes. LTB and PGE regulation of lymphocytes is diverse and depends on the interaction of lymphocytes with other cells. Importantly, both LTB and PGE are essential regulators of T cell antitumor activity. These LMs are attractive therapeutic targets to control dysregulated innate and adaptive immune responses, promote lymphocyte antitumor activity, and prevent tumor immune evasion.
Topics: Animals; Dinoprostone; Eicosanoids; Humans; Inflammation; Leukotriene B4; Lymphocytes
PubMed: 30477730
DOI: 10.1016/j.tibs.2018.10.007 -
Cancer Metastasis Reviews Sep 2021Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell "debris" which can promote tumor progression. Thus, therapy... (Review)
Review
Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell "debris" which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.
Topics: Antineoplastic Agents; Cell Line, Tumor; Cytokines; Eicosanoids; Humans; MicroRNAs; Neoplasms; Tumor Microenvironment
PubMed: 34665387
DOI: 10.1007/s10555-021-09998-8 -
Frontiers in Immunology 2023Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated...
Allergic inflammation of the airways such as allergic asthma is a major health problem with growing incidence world-wide. One cardinal feature in severe type 2-dominated airway inflammation is the release of lipid mediators of the eicosanoid family that can either promote or dampen allergic inflammation. Macrophages are key producers of prostaglandins and leukotrienes which play diverse roles in allergic airway inflammation and thus require tight control. Using RNA- and ATAC-sequencing, liquid chromatography coupled to mass spectrometry (LC-MS/MS), enzyme immunoassays (EIA), gene expression analysis and models, we show that the aryl hydrocarbon receptor (AhR) contributes to this control transcriptional regulation of lipid mediator synthesis enzymes in bone marrow-derived as well as in primary alveolar macrophages. In the absence or inhibition of AhR activity, multiple genes of both the prostaglandin and the leukotriene pathway were downregulated, resulting in lower synthesis of prostanoids, such as prostaglandin E2 (PGE), and cysteinyl leukotrienes, e.g., Leukotriene C4 (LTC). These AhR-dependent genes include encoding for the enzyme cyclooxygenase 1 (COX1) and encoding for the arachidonate 5-lipoxygenase (5-LO) both of which major upstream regulators of the prostanoid and leukotriene pathway, respectively. This regulation is independent of the activation stimulus and partially also detectable in unstimulated macrophages suggesting an important role of basal AhR activity for eicosanoid production in steady state macrophages. Lastly, we demonstrate that AhR deficiency in hematopoietic but not epithelial cells aggravates house dust mite induced allergic airway inflammation. These results suggest an essential role for AhR-dependent eicosanoid regulation in macrophages during homeostasis and inflammation.
Topics: Humans; Chromatography, Liquid; Dinoprostone; Eicosanoids; Inflammation; Leukotrienes; Macrophages, Alveolar; Prostaglandins; Receptors, Aryl Hydrocarbon; Tandem Mass Spectrometry
PubMed: 37081886
DOI: 10.3389/fimmu.2023.1157373 -
Pharmacology & Therapeutics Feb 2021Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of... (Review)
Review
Inflammation in the tumor microenvironment is a hallmark of cancer and is recognized as a key characteristic of carcinogens. However, the failure of resolution of inflammation in cancer is only recently being understood. Products of arachidonic acid and related fatty acid metabolism called eicosanoids, including prostaglandins, leukotrienes, lipoxins, and epoxyeicosanoids, critically regulate inflammation, as well as its resolution. The resolution of inflammation is now appreciated to be an active biochemical process regulated by endogenous specialized pro-resolving lipid autacoid mediators which combat infections and stimulate tissue repair/regeneration. Environmental and chemical human carcinogens, including aflatoxins, asbestos, nitrosamines, alcohol, and tobacco, induce tumor-promoting inflammation and can disrupt the resolution of inflammation contributing to a devastating global cancer burden. While mechanisms of carcinogenesis have focused on genotoxic activity to induce mutations, nongenotoxic mechanisms such as inflammation and oxidative stress promote genotoxicity, proliferation, and mutations. Moreover, carcinogens initiate oxidative stress to synergize with inflammation and DNA damage to fuel a vicious feedback loop of cell death, tissue damage, and carcinogenesis. In contrast, stimulation of resolution of inflammation may prevent carcinogenesis by clearance of cellular debris via macrophage phagocytosis and inhibition of an eicosanoid/cytokine storm of pro-inflammatory mediators. Controlling the host inflammatory response and its resolution in carcinogen-induced cancers will be critical to reducing carcinogen-induced morbidity and mortality. Here we review the recent evidence that stimulation of resolution of inflammation, including pro-resolution lipid mediators and soluble epoxide hydrolase inhibitors, may be a new chemopreventive approach to prevent carcinogen-induced cancer that should be evaluated in humans.
Topics: Carcinogenesis; Carcinogens; Eicosanoids; Humans; Inflammation; Inflammation Mediators; Neoplasms; Tumor Microenvironment
PubMed: 32891711
DOI: 10.1016/j.pharmthera.2020.107670 -
Immunological Reviews Mar 2015A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen... (Review)
Review
A major approach for immunologic intervention in tuberculosis involves redirecting the outcome of the host immune response from the induction of disease to pathogen control. Cytokines and lipid mediators known as eicosanoids play key roles in regulating this balance and as such represent important targets for immunologic intervention. While the evidence for cytokine/eicosanoid function derives largely from the investigation of murine and zebrafish experimental infection models, clinical studies have confirmed the existence of many of the same pathways in tuberculosis patients. Here, we summarize new data that reveal important intersections between the cytokine and eicosanoid networks in the host response to mycobacteria and discuss how targeting this crosstalk can promote resistance to lethal Mycobacterium tuberculosis infection. This approach could lead to new host-directed therapies to be used either as an adjunct for improving the efficacy of standard antibiotic treatment or for the management of drug-resistant infections.
Topics: Animals; Antitubercular Agents; Biomarkers; Cytokines; Eicosanoids; Host-Pathogen Interactions; Humans; Inflammation Mediators; Mycobacterium tuberculosis; Signal Transduction; Tuberculosis
PubMed: 25703565
DOI: 10.1111/imr.12249