8-11-14-eicosatrienoic-acid and Inflammation

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Arachidonic Acid; Chronic Disease; Fatty Acid Desaturases; Fatty Acids, Omega-6; Humans; Inflammation

Mead acid (MA, 5,8,11-eicosatrienoic acid) is an n-9 polyunsaturated fatty acid (PUFA) and a marker of essential fatty acid deficiency, but nonetheless generally draws little attention. MA is distributed in various normal tissues and can be converted to several specific lipid mediators by lipoxygenase and cyclooxygenase. Recent pathological and epidemiological studies on MA raise the possibility of its effects on inflammation, cancer, dermatitis and cystic fibrosis, suggesting it is an endogenous multifunctional PUFA. This review summarizes the biosynthesis, presence, metabolism and physiological roles of MA and its relation to various diseases, as well as the significance of MA in PUFA metabolism.

Topics: 8,11,14-Eicosatrienoic Acid; Fatty Acids, Unsaturated; Humans; Inflammation

There is increasing evidence from various scientific groups that hepoxilins represent novel inflammatory mediators. In vitro studies have shown that the hepoxilins cause mobilization of intracellular calcium in human neutrophils, cause plasma leakage, and potently stimulate chemotaxis of human neutrophils. In vivo, the hepoxilin pathway is activated in conditions of inflammation, e.g. after pathogen infection, in inflamed conditions (psoriasis, arthritis), and hepoxilins promote inflammatory hyperalgesia and allodynia. Although much work has demonstrated an effect of hepoxilins on neutrophils, the hepoxilin pathway has been demonstrated in a variety of tissues, including the lung, brain, pituitary, pancreatic islets, skin, etc. A genetic defect linked to a deficiency in hepoxilin formation has been described and believed to be responsible for the scaly skin observed in ichthyosis. Despite their biological and chemical instability, the involvement of the hepoxilin pathway in pathology has been demonstrated in vitro and in vivo through either isolation of the hepoxilins themselves (or their metabolites) or implied through the use of stable hepoxilin analogs. These analogs have additionally shown efficacy in animal models of lung fibrosis, cancer, thrombosis and diabetes. Research on these compounds has merely scratched the surface, but results published to date have suggested that the hepoxilin pathway is a distinct and novel pathway leading to inflammation and hepoxilin antagonists may provide the means of controlling early aspects of the acute inflammatory phase. This article is part of a Special Issue entitled "Oxygenated metabolism of PUFA: analysis and biological relevance".

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Drug Design; Humans; Inflammation; Inflammation Mediators; Leukotrienes; Molecular Structure; Molecular Targeted Therapy; Neoplasms; Signal Transduction; Structure-Activity Relationship

This review summarizes recent developments in the role of soluble mediators of inflammation, particularly arachidonic acid metabolites, in inflammatory bowel disease (IBD).. The role of prostaglandin E2 in immune regulation has been better defined. Prostaglandin E2 promotes not only immune tolerance and epithelial homeostasis but also the proinflammatory Th17 pathway. Prostaglandin D2 has been established as promoting the resolution of inflammation in the gastrointestinal mucosa. The 12-lipoxygenase product hepoxilin A3 mediates the migration of neutrophils from the mucosa into the lumen.. Recent studies of soluble mediators, especially arachidonic acid metabolites, have defined their proinflammatory and anti-inflammatory roles in IBD.

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cell Movement; Dinoprostone; Humans; Inflammation; Inflammatory Bowel Diseases; Intestinal Mucosa; Neutrophils; Prostaglandin D2; Signal Transduction; Th17 Cells

Considerable arguments remain regarding the diverse biological activities of polyunsaturated fatty acids (PUFA). One of the most interesting but controversial dietary approaches focused on the diverse function of dihomo-dietary γ-linolenic acid (DGLA) in anti-inflammation and anti-proliferation diseases, especially for cancers. This strategy is based on the ability of DGLA to interfere in cellular lipid metabolism and eicosanoid (cyclooxygenase and lipoxygenase) biosynthesis. Subsequently, DGLA can be further converted by inflammatory cells to 15-(S)-hydroxy-8,11,13-eicosatrienoic acid and prostaglandin E1 (PGE1). This is noteworthy because these compounds possess both anti-inflammatory and anti-proliferative properties. PGE1 could also induce growth inhibition and differentiation of cancer cells. Although the mechanism of DGLA has not yet been elucidated, it is significant to anticipate the antitumor potential benefits from DGLA.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Antineoplastic Agents; Cell Differentiation; Cell Proliferation; Humans; Inflammation; Neoplasms; Oxidation-Reduction

The soluble epoxide hydrolase (sEH) enzyme regulates the levels of endogenous epoxygenated fatty acid (EFA) lipid metabolites by rapidly degrading these molecules. The EFAs have pleiotropic biological activities including the modulation of nociceptive signaling. Recent findings indicate that the EFAs, in particular the arachidonic acid (AA) derived epoxyeicosatrienoic acids (EETs), the docosahexaenoic acid (DHA) derived epoxydocosapentaenoic acids (EpDPEs) and eicosapentaenoic acid (EPA) derived epoxyeicosatetraenoic acids (EpETEs) are natural signaling molecules. The tight regulation of these metabolites speaks to their importance in regulating biological functions. In the past several years work on EFAs in regard to their activities in the nervous system evolved to demonstrate that these molecules are anti-inflammatory and anti-nociceptive. Here we focus on the recent advances in understanding the effects of sEH inhibition and increased EFAs on the nociceptive system and their ability to reduce pain. Evidence of their role in modulating pain signaling is given by their direct application and by inhibiting their degradation in various models of pain. Moreover, there is mounting evidence of EFAs role in the crosstalk between major nociceptive and anti-nociceptive systems which is reviewed herein. Overall the fundamental knowledge generated within the past decade indicates that orally bioavailable small molecule inhibitors of sEH may find a place in the treatment of a number of diverse painful conditions including inflammatory and neuropathic pain.

Topics: 8,11,14-Eicosatrienoic Acid; Analgesics, Non-Narcotic; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Cyclooxygenase 2; Docosahexaenoic Acids; Eicosapentaenoic Acid; Enzyme Inhibitors; Epoxide Hydrolases; Humans; Hyperalgesia; Inflammation; Mice; Mice, Knockout; Nervous System; Nociception; Pain; Rats; Rats, Sprague-Dawley; Signal Transduction

Inflammation and angiogenesis in the tumor microenvironment are increasingly implicated in tumorigenesis. Endogenously produced lipid autacoids, locally acting small-molecule mediators, play a central role in inflammation and tissue homeostasis. These lipid mediators, collectively referred to as eicosanoids, have recently been implicated in cancer. Although eicosanoids, including prostaglandins and leukotrienes, are best known as products of arachidonic acid metabolism by cyclooxygenases and lipoxygenases, arachidonic acid is also a substrate for another enzymatic pathway, the cytochrome P450 (CYP) system. This eicosanoid pathway consists of two main branches: ω-hydroxylases which converts arachidonic acid to hydroxyeicosatetraenoic acids (HETEs) and epoxygenases which converts it to four regioisomeric epoxyeicosatrienoic acids (EETs; 5,6-EET, 8,9-EET, 11,12-EET, and 14,15-EET). EETs regulate inflammation and vascular tone. The bioactive EETs are produced predominantly in the endothelium and are mainly metabolized by soluble epoxide hydrolase to less active dihydroxyeicosatrienoic acids. EET signaling was originally studied in conjunction with inflammatory and cardiovascular disease. Arachidonic acid and its metabolites have recently stimulated great interest in cancer biology. To date, most research on eicosanoids in cancer has focused on the COX and LOX pathways. In contrast, the role of cytochrome P450-derived eicosanoids, such as EETs and HETEs, in cancer has received little attention. While CYP epoxygenases are expressed in human cancers and promote human cancer metastasis, the role of EETs (the direct products of CYP epoxygenases) in cancer remains poorly characterized. In this review, the emerging role of EET signaling in angiogenesis, inflammation, and cancer is discussed.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cell Transformation, Neoplastic; Cytochrome P-450 Enzyme System; Humans; Inflammation; Neoplasms; Neovascularization, Pathologic; Signal Transduction; Tumor Microenvironment

Bacterial infections at epithelial surfaces, such as those that line the gut and the lung, stimulate the migration of neutrophils through the co-ordinated actions of chemoattractants secreted from pathogen-stimulated epithelial cells. One such factor involved in attracting polymorphonuclear leukocytes across the epithelium and into the lumen has until recently remained elusive. In 2004, we identified the eicosanoid, hepoxilin A(3), to be selectively secreted from the apical surface of human intestinal or lung epithelial cells stimulated with Salmonella enterica serotype Typhimurium or Pseudomonas aeruginosa, respectively. In this role, the function of hepoxilin A(3) is to guide neutrophils, via the establishment of a gradient, across the epithelial tight junction complex. Interestingly, interruption of the synthetic pathway of hepoxilin A(3) blocks the apical release of hepoxilin A(3)in vitro and the transmigration of neutrophils induced by S. typhimurium both in in vitro and in vivo models of inflammation. Such results have led to the discovery of a completely novel pathway that is not only critical for responses to bacterial pathogens but also has broad implications for inflammatory responses affecting mucosal surfaces in general. Thus, the objective of this review was to highlight the recent findings that implicate hepoxilin A(3) as a key regulator of mucosal inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acids; Chemotaxis; Humans; Inflammation; Inflammation Mediators; Neutrophils

Cytochrome P450 epoxygenases metabolize arachidonic acid to biologically active eicosanoids. Primary epoxidation products are four regioisomers of cis-epoxyeicosatrienoic acid (EET), 5,6-, 8,9-, 11,12-, and 14,15-EET. One of the predominant epoxygenase isoforms involved in EET formation belongs to the CYP2 gene family. In humans, the P450 epoxygenase, CYP2J2, is expressed in the cardiovascular system, namely the endothelium, vascular smooth muscle, and cardiomyocyte. CYP2J2 possesses vascular protective effects, which include but are not limited to, protection against ischemia-reperfusion injury, suppression of reactive oxygen species following hypoxia-reoxygenation, inhibition of the pro-inflammatory transcription factor, nuclear factor-kappaB (NF-kappaB), attenuation of vascular smooth muscle migration, and enhancement of a fibrinolytic pathway. Although regioisomers of EET elicit these effects to varying degrees, 11,12-EET appears to be the most potent with respect to anti-inflammatory, anti-migratory, and pro-fibrinolytic effects. Thus, CYP2J2 and its derived arachidonic acid metabolites may play important roles in regulating vascular function under normal and pathophysiological conditions.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Cell Movement; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Eicosanoids; Fibrinolysis; Humans; Inflammation; Isoenzymes; Models, Biological; Muscle, Smooth, Vascular; Myocytes, Cardiac; NF-kappa B; Oxygenases; Protective Agents; Stereoisomerism; Vasodilation

Until recently, studies on the role of the metabolites of arachidonic acid (AA), eicosanoids in fever have primarily focused on prostaglandins, prostaglandin E2 (PGE2) in particular, derived from the pathway related to cyclooxygenases (COX). COX exists in two known isoforms; a constitutive COX-1, and COX-2, which is inducible upon the action of pyrogens. Data accumulated in our laboratories suggest a thermoregulatory role for two other pathways of arachidonate metabolism; 5-lipoxygenase (5-LOX) and cytochrome P-450 (epoxygenase). We have demonstrated that leukotrienes (LTs; 5-LOX-derived eicosanoids) and various isomers of epoxyeicosatrienoic acids (EETs; epoxygenase-derived eicosanoids) contribute to the process of endogenous antipyresis or cryogenesis, which limits the height of fever. In support of this are several lines of evidence based on both in vivo and in vitro experiments. 1) Intracerebroventricular (icv) injections of LTC4 at nanomolar concentrations cause a dose-dependent decrease of body temperature (Tb) in mice. 2) Lipopolysaccharide (LPS)-induced anapyrexia in mice is preceded and accompanied by elevation in hypothalamic cysteinyl-LT (CysLT) production. 3) The inhibitor of LT synthesis MK-886 suppresses both of these processes. 4) EETs as well as inducers of the epoxygenase attenuate, whereas inhibitors of epoxygenase enhance the LPS-induced fever in rats. 5) One of the isomers of EET, 11,12-EET, in in vitro studies inhibited both the generation of PGE2 and IL-6 in monocytes stimulated with LPS. These results, together with a well-established pyrogenic role of PGE2, indicate that AA cascade may be regarded as an endogenous system to regulate the temperature response upon disease. COX, 5-LOX, and epoxygenase products may act at the level of hypothalamus as proximal mediators of, respectively, fever (PGE2) or cryogenesis (CysLTs and EETs), or indirectly by influencing the other endogenous cryogens and pyrogens.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 5-Lipoxygenase; Body Temperature; Cyclooxygenase 1; Cyclooxygenase 2; Cytokines; Eicosanoids; Feedback, Physiological; Fever; Humans; Hypothalamus; Indoles; Inflammation; Leukotrienes; Lipopolysaccharides; Macrophages; Mice; Protein Isoforms; Rats

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Arachidonic Acid; Biological Factors; Cell Adhesion Molecules; Cytochrome P-450 Enzyme System; Endothelium, Vascular; Humans; Inflammation; Protein Isoforms; Vasodilation

Evidence obtained from experiments in vitro and in vivo suggests that certain unsaturated fatty acids (FA) may be safe and effective antiinflammatory and immunomodulatory agents. Generation of a unique eicosanoid profile with different biological effects by administration of FA precursors other than arachidonic acid is one approach under investigation. In addition to their role as eicosanoid precursors, FA are of major importance in maintaining cell membrane structure, are key determinants of membrane bound enzyme activity and receptor expression. FA can exert these functions directly and therefore may themselves be important regulators of immune responses. For example, certain FA influence cytokine production and proliferation of human T lymphocytes in a manner that is direct and not due to their conversion to eicosanoids. The observations indicate that FA can modulate immune responses by acting directly on T-cells and suggest that alteration of cellular FA may be a worthwhile approach to control of inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Adjuvants, Immunologic; Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Arachidonic Acid; Cells, Cultured; Cytokines; Dietary Fats; Eicosanoids; Fatty Acids; Fatty Acids, Essential; Humans; Immunity, Cellular; Inflammation; Interleukin-2; Membrane Lipids; Signal Transduction; T-Lymphocytes

Much attention has recently been paid to the possible benefits of increasing the intake of eicosapentaenoic acid (EPA) by consuming fish oil. However, this can have adverse effects such as raising cholesterol levels in patients with hyperlipidaemia and causing a deterioration in glucose tolerance. High doses of EPA given to Westerners also lower levels of dihomogammalinolenic acid (DGLA), a substance with a wide range of desirable cardiovascular and antiinflammatory actions. This lowering of DGLA does not occur in Eskimos who consume large amounts of EPA, indicating that there may be differences in essential fatty acid metabolism between Westerners and Eskimos. Therapeutic strategies are required which raise both EPA and DGLA and which do not raise EPA at the cost of lowering DGLA.

Topics: 8,11,14-Eicosatrienoic Acid; Cardiovascular Diseases; Cholesterol; Dietary Fats, Unsaturated; Drug Interactions; Eicosapentaenoic Acid; Fatty Acids, Essential; Humans; Inflammation

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acids; Eicosanoids; Epoxide Hydrolases; Humans; Inflammation; Kidney; Renal Insufficiency, Chronic; Ureteral Obstruction

Epoxyeicosatrienoic acids (EET) facilitate regeneration in different tissues, and their benefit in dermal wound healing has been proven under normal conditions. In this study, we investigated the effect of 11,12 EET on dermal wound healing in diabetes. We induced diabetes by i.p. injection of streptozotocin 2 weeks prior to wound creation on the dorsal side of the mouse ear. 11,12 EET was applied every second day on the wound, whereas the control groups received only solvent. Epithelialization was monitored every second day

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Diabetes Complications; Diabetes Mellitus, Experimental; Drug Evaluation, Preclinical; Inflammation; Male; Mice; Neovascularization, Physiologic; Wound Healing

Dihomo-γ-linolenic acid (DGLA, C20: 3n-6) is known to have an anti-inflammatory activity, but its range of effects was not well studied because of its limited natural sources. We addressed these issues by constructing an yeast

Topics: 8,11,14-Eicosatrienoic Acid; Acetone; Administration, Oral; Animals; Cell- and Tissue-Based Therapy; Chemokine CCL2; Chemokines; Dermatitis, Allergic Contact; Dinitrofluorobenzene; Ear, External; Female; Immunization; Inflammation; Interferon-gamma; Mice; Oleic Acid; Olive Oil; Saccharomyces cerevisiae

Lipid mediators (LMs) play a pivotal role in the induction and resolution of inflammation. To identify and elucidate their involvement during virus infection, multiple reaction monitoring (MRM) based liquid chromatography-tandem mass spectrometry lipidomic profiling of 62 lipid species was performed in this study. Results show that RAW264.7 macrophages differentially produce specific LMs signals depending on difference in virus pathogenicity. Integration of large-scale lipidomics with targeted gene expression data revealed mediators, such as RVD3, 18-HEPE, 11(12)-EET etc. correlated with the pathogenic phase of the infection. The herpes simplex virus (HSV)-induced keratitis model demonstrates that 11(12)-EET treatment represents a novel alternative for treating viral infection.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Antiviral Agents; Chlorocebus aethiops; Chromatography, Liquid; Cornea; Inflammation; Keratitis, Herpetic; Lipidomics; Male; Mice; Mice, Inbred BALB C; RAW 264.7 Cells; Simplexvirus; Tandem Mass Spectrometry; Vero Cells; Vesiculovirus; Virus Replication

Microalgae have been considered as a renewable source of nutritional, cosmetic and pharmaceutical compounds. The ability to produce health-beneficial long-chain polyunsaturated fatty acids (LC-PUFA) is of high interest. LC-PUFA and their metabolic lipid mediators, modulate key inflammatory pathways in numerous models. In particular, the metabolism of arachidonic acid under inflammatory challenge influences the immune reactivity of macrophages. However, less is known about another omega-6 LC-PUFA, dihomo-γ-linolenic acid (DGLA), which exhibits potent anti-inflammatory activities, which contrast with its delta-5 desaturase product, arachidonic acid (ARA). In this work, we examined whether administrating DGLA would modulate the inflammatory response in the RAW264.7 murine macrophage cell line. DGLA was applied for 24 h in the forms of carboxylic (free) acid, ethyl ester, and ethyl esters obtained from the DGLA-accumulating delta-5 desaturase mutant strain P127 of the green microalga

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Dose-Response Relationship, Drug; Gene Expression Regulation; Inflammation; Lipopolysaccharides; Macrophages; Mice; Microalgae; Prostaglandins; RAW 264.7 Cells

Zika virus (ZIKV) has emerged as one of the most medically relevant viral infections of the past decades; the devastating effects of this virus over the developing brain are a major matter of concern during pregnancy. Although the connection with congenital malformations are well documented, the mechanisms by which ZIKV reach the central nervous system (CNS) and the causes of impaired cortical growth in affected fetuses need to be better addressed. We performed a non-invasive, metabolomics-based screening of saliva from infants with congenital Zika syndrome (CZS), born from mothers that were infected with ZIKV during pregnancy. We were able to identify three biomarkers that suggest that this population suffered from an important inflammatory process; with the detection of mediators associated with glial activation, we propose that microcephaly is a product of immune response to the virus, as well as excitotoxicity mechanisms, which remain ongoing even after birth.

Topics: 8,11,14-Eicosatrienoic Acid; Biomarkers; Female; Fetal Development; Fetus; Humans; Infant; Infant, Newborn; Inflammation; Longitudinal Studies; Male; Metabolomics; Microcephaly; Mothers; Parturition; Pregnancy; Pregnancy Complications, Infectious; Saliva; Virus Diseases; Zika Virus; Zika Virus Infection

PUFA might modulate inflammatory responses involved in the development of severe dengue. We aimed to examine whether serum PUFA concentrations in patients diagnosed with dengue fever (DF) were related to the risk of progression to dengue haemorrhagic fever/dengue shock syndrome (DHF/DSS). A secondary aim was to assess correlations between fatty acids (FA) and inflammatory biomarkers in patients with DF. We conducted a prospective case-control study nested within a cohort of patients who were diagnosed with DF and followed during the acute episode. We compared the distribution of individual FA (% of total FA) at onset of fever between 109 cases who progressed to DHF/DSS and 235 DF non-progressing controls using unconditional logistic regression. We estimated correlations between baseline FA and cytokine concentrations and compared FA concentrations between the acute episode and >1 year post-convalescence in a subgroup. DHA was positively related to progression to DHF/DSS (multivariable adjusted OR (AOR) for DHA in quintile 5 v. 1=5·34, 95 % CI 2·03, 14·1; P trend=0·007). Dihomo-γ-linolenic acid (DGLA) was inversely associated with progression (AOR for quintile 5 v. 1=0·30, 95 % CI 0·13, 0·69; P trend=0·007). Pentadecanoic acid concentrations were inversely related to DHF/DSS. Correlations of PUFA with cytokines at baseline were low. PUFA were lower during the acute episode than in a disease-free period. In conclusion, serum DHA in patients with DF predicts higher odds of progression to DHF/DSS whereas DGLA and pentadecanoic acid predict lower odds.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; Case-Control Studies; Child; Cytokines; Dengue; Disease Progression; Docosahexaenoic Acids; Fatty Acids; Female; Fever; Hemorrhagic Fevers, Viral; Humans; Inflammation; Logistic Models; Male; Nutritional Status; Odds Ratio; Prospective Studies; Severe Dengue; Severity of Illness Index; Young Adult

Polyunsaturated fatty acids (PUFAs) take part in various biological events linked to the pathogenesis of venous thromboembolism (VTE), including inflammation, endothelial dysfunction, and hypercoagulability. Several studies have demonstrated the association between PUFAs and the occurrence of VTE. However, the role of PUFAs in the pathogenesis of VTE remains unclear.. We enrolled 45 patients with acute VTE and 37 age-, gender-, and body mass index-matched healthy volunteers to examine their PUFA levels. Serum omega 3 (eicosapentaenoic acid: EPA and docosahexaenoic acid: DHA) and omega 6 (dihomogammalinolenic acid: DGLA and arachidonic acid: AA) fatty acids levels were measured within 24 h of admission.. Patients with VTE showed significantly higher AA and lower EPA levels, and lower EPA/AA ratios than the controls. Multivariate analysis revealed that AA was an independent marker for VTE. In addition, we divided the patients based on their median age (58 years old). The younger patients with VTE showed significantly lower EPA/AA levels than their age-matched controls, whereas older patients with VTE showed a significantly higher AA/DGLA levels than the older controls.. High serum AA levels and low EPA levels are associated with the development of acute VTE, suggesting that the imbalance of PUFAs may be a potential therapeutic target for preventing acute VTE.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arachidonic Acid; Biomarkers; Blood Coagulation; Body Mass Index; Case-Control Studies; Diet; Eicosapentaenoic Acid; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Healthy Volunteers; Humans; Inflammation; Male; Middle Aged; Multivariate Analysis; Prevalence; Risk Factors; Sex Factors; Venous Thromboembolism

CYP2J2 is highly expressed in cardiovascular tissue including the heart and vascular endothelial cells. CYP2J2 and the EETs have been shown owning diverse biological effects. Our previous study found that ophiopogonin D (OP-D) suppressed drug-induced endoplasmic reticulum (ER) stress by upregulating the levels of CYP2J3/EETs in cardiomyocytes. The aim of this research was to investigate whether CYP2J2/EETs-PPARα pathway involved in endothelium protective effects of OP-D in human umbilical vein endothelial cells (HUVECs). The results showed that OP-D significantly inhibited Ang II induced NF-κB nuclear translocation, IκBα down-regulation and activation of pro-inflammatory cytokines (TNF-α, IL-6 and VCAM-1) by increasing the expression of CYP2J2/EETs and PPARα in HUVECs. Furthermore, treatment with exogenous 11,12-EET attenuated endothelial inflammation induced by Ang II as evidenced by inhibited NF-κB nuclear translocation, increased IκBα expression and decreased inflammation factor level. Finally, the activation of NF-κB nuclear translocation induced by Ang II was also markedly suppressed by fenofibrate. Co-incubation with 6-(2-proparglyloxyphenyl) hexanoic acid (PPOH) and PPARα inhibitor GW6471 before drug treatment abolished the endothelium protective effects of OP-D. Taken together, these data suggest that OP-D has the endothelial protective effect through activation of CYP2J and increasing EETs, and PPARα involves in this process.

Topics: 8,11,14-Eicosatrienoic Acid; Angiotensin II; Cells, Cultured; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; NF-kappa B; PPAR alpha; Protein Transport; Saponins; Spirostans

Neutrophil breach of the mucosal surface is a common pathological consequence of infection. We present an advanced co-culture model to explore neutrophil transepithelial migration utilizing airway mucosal barriers differentiated from primary human airway basal cells and examined by advanced imaging. Human airway basal cells were differentiated and cultured at air-liquid interface (ALI) on the underside of 3 µm pore-sized transwells, compatible with the study of transmigrating neutrophils. Inverted ALIs exhibit beating cilia and mucus production, consistent with conventional ALIs, as visualized by micro-optical coherence tomography (µOCT). µOCT is a recently developed imaging modality with the capacity for real time two- and three-dimensional analysis of cellular events in marked detail, including neutrophil transmigratory dynamics. Further, the newly devised and imaged primary co-culture model recapitulates key molecular mechanisms that underlie bacteria-induced neutrophil transepithelial migration previously characterized using cell line-based models. Neutrophils respond to imposed chemotactic gradients, and migrate in response to Pseudomonas aeruginosa infection of primary ALI barriers through a hepoxilin A3-directed mechanism. This primary cell-based co-culture system combined with µOCT imaging offers significant opportunity to probe, in great detail, micro-anatomical and mechanistic features of bacteria-induced neutrophil transepithelial migration and other important immunological and physiological processes at the mucosal surface.

Topics: 8,11,14-Eicosatrienoic Acid; Cell Culture Techniques; Cell Line; Cell Movement; Cell Polarity; Chemotaxis, Leukocyte; Coculture Techniques; Epithelial Cells; Fluorescent Antibody Technique; Humans; Inflammation; Neutrophil Infiltration; Neutrophils; Respiratory Mucosa

Recurrent Pseudomonas aeruginosa infections coupled with robust, damaging neutrophilic inflammation characterize the chronic lung disease cystic fibrosis (CF). The proresolving lipid mediator, 15-epi lipoxin A

Topics: 8,11,14-Eicosatrienoic Acid; Bacterial Proteins; Bronchoalveolar Lavage Fluid; Cell Line; Crystallography, X-Ray; Cystic Fibrosis; Humans; Inflammation; Lipoxins; Lung Diseases; Neutrophil Activation; Neutrophils; Pseudomonas aeruginosa; Pseudomonas Infections; Retrospective Studies; Virulence Factors

Depression is a major public health challenge worldwide, and polyunsaturated fatty acids (PUFAs), especially n-3 PUFAs, have been found to inversely associate with the risk of depression. However, only few cross-sectional studies have investigated the association between dihomo-γ-linolenic acid (DGLA), an n-6 PUFA with anti-inflammatory effects, and depression. The aims of the present study were to examine an association between serum DGLA and the risk of depression, and to study whether the potential association is mediated via inflammation.. A 20-year prospective Kuopio Ischaemic Heart Disease Risk Factor (KIHD) follow-up study was conducted from 1984 to 1989 with 2179 middle-aged and older Finnish men (42-60 years old at baseline). The baseline concentrations of serum fatty acids, including DGLA, were determined. A hospital discharge diagnosis of depression was used as the main outcome and obtained from linkage to National Hospital Discharge Register. Serum C-reactive protein (CRP) levels were measured to assess inflammation.. An inverse association between serum DGLA concentration and incidence of depression was found after adjustment for several potential confounders (Hazard ratio HR 0.53, CI 0.36-0.79, P=0.002). The association between DGLA and depression was not dependent on inflammation (P-interaction=0.618).. Our findings may not be generalizable to individuals below middle-age or women. Moreover, we were unable to consider cases with mild depression in the longitudinal setting.. Higher serum DGLA concentrations may predict lower risk of develop depression in elderly men. Further studies are warranted to address potential mechanisms as mechanism behind this association remains unclear.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; C-Reactive Protein; Depression; Finland; Follow-Up Studies; Humans; Incidence; Inflammation; Male; Middle Aged; Prospective Studies; Serum

Cytochrome P450 (CYP)-derived epoxyeicosatrienoic acids (EETs) exhibit potent cardiovascular protective effects in preclinical models, and promoting the effects of EETs has emerged as a potential therapeutic strategy for coronary artery disease (CAD). The relationship between circulating EET levels and CAD extent in humans, however, remains unknown. A panel of free (unesterified) plasma eicosanoid metabolites was quantified in 162 patients referred for coronary angiography, and associations with extent of CAD [no apparent CAD (N = 39), nonobstructive CAD (N = 51), and obstructive CAD (N = 72)] were evaluated. A significant relationship between free EET levels and CAD extent was observed (P = 0.003) such that the presence of obstructive CAD was associated with lower circulating EET levels. This relationship was confirmed in multiple regression analysis where CAD extent was inversely and significantly associated with EET levels (P = 0.013), and with a biomarker of EET biosynthesis (P < 0.001), independent of clinical and demographic factors. Furthermore, quantitative enrichment analysis revealed that these associations were the most pronounced compared with other eicosanoid metabolism pathways. Collectively, these findings suggest that the presence of obstructive CAD is associated with lower EET metabolite levels secondary to suppressed EET biosynthesis. Novel strategies that promote the effects of EETs may have therapeutic promise for patients with obstructive CAD.

Topics: 8,11,14-Eicosatrienoic Acid; Adult; Aged; Arachidonic Acid; Arachidonic Acids; Biomarkers; Coronary Angiography; Coronary Artery Disease; Cytochrome P-450 Enzyme System; Female; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Male; Metabolomics; Middle Aged

Epoxyeicosatrienoic acids (EETs) are metabolic products of free arachidonic acid, which are produced through cytochrome P-450 (CYP) epoxygenases. EETs have anti-inflammatory, antiapoptotic, and antioxidative activities. However, the effect of EETs on cigarette smoke-induced lung inflammation is not clear. Autophagy is believed to be involved in the pathogenesis of chronic obstructive pulmonary disease. In addition, nuclear erythroid-related factor 2 (Nrf2), a transcription factor that regulates many antioxidant genes, is thought to regulate antioxidant defenses in several lung diseases. In addition, interaction between EETs, autophagy, and Nrf2 has been reported. The aim of this study was to explore the effect of 14,15-EET on cigarette smoke condensate (CSC)-induced inflammation in a human bronchial epithelial cell line (Beas-2B), and to determine whether the underlying mechanisms involved in the regulation of Nrf2 through inhibition of autophagy. Autophagy and expression of autophagy signaling pathway proteins (LC3B, p62, PI3K, Akt, p-Akt, and p-mTOR) and anti-inflammatory proteins (Nrf2 and HO-1) were assessed via Western blot analysis. Autophagosomes and autolysosomes were detected by adenoviral mRFP-GFP-LC3 transfection. Inflammatory factors (IL-6, IL-8, and MCP-1) were detected by ELISA. Lentiviral vectors carrying p62 short hairpin RNA were used to interfere with p62 expression to evaluate the effect of p62 on Nrf2 expression. Nrf2 expression was determined through immunocytochemistry. 14,15-EET treatment resulted in a significant reduction in IL-6, IL-8, and MCP-1 secretion, and increased accumulation of Nrf2 and expression of HO-1. In addition, 14,15-EET inhibited CSC-induced autophagy in Beas-2B cells. The mechanism of the anti-inflammatory effect of 14,15-EET involved inhibition of autophagy and an increase in p62 levels, followed by translocation of Nrf2 into the nucleus, which then upregulated expression of the antioxidant enzyme HO-1. 14,15-EET protects against CSC-induced lung inflammation by promoting accumulation of Nrf2 via inhibition of autophagy.

Topics: 8,11,14-Eicosatrienoic Acid; Anti-Inflammatory Agents; Autophagy; Cell Line; Cell Nucleus; Epithelial Cells; Gene Knockdown Techniques; Heme Oxygenase-1; Humans; Inflammation; Inflammation Mediators; Lung; NF-E2-Related Factor 2; Phosphatidylinositol 3-Kinases; Protein Transport; RNA-Binding Proteins; Signal Transduction; Smoking; TOR Serine-Threonine Kinases; Up-Regulation

Obesity is now recognized as a state of chronic low-grade inflammation and is called as metabolic inflammation. Delta-5 desaturase (D5D) is an enzyme that metabolizes dihomo-γ-linolenic acid (DGLA) to arachidonic acid (AA). Thus, D5D inhibition increases DGLA (precursor to anti-inflammatory eicosanoids) while decreasing AA (precursor to pro-inflammatory eicosanoids), and could result in synergistic improvement in the low-grade inflammatory state. Here, we demonstrate reduced insulin resistance and the anti-obesity effect of a D5D selective inhibitor (compound-326), an orally active small-molecule, in a high-fat diet-induced obese (DIO) mouse model. In vivo D5D inhibition was confirmed by determining changes in blood AA/DGLA profiles. In DIO mice, chronic treatment with compound-326 lowered insulin resistance and caused body weight loss without significant impact on cumulative calorie intake. Decreased macrophage infiltration into adipose tissue was expected from mRNA analysis. Increased daily energy expenditure was also observed following administration of compound-326, in line with sustained body weight loss. These data indicate that the novel D5D selective inhibitor, compound-326, will be a new class of drug for the treatment of obese and diabetic patients.

Topics: 8,11,14-Eicosatrienoic Acid; Adiponectin; Adipose Tissue; Animals; Arachidonic Acid; Body Weight; Delta-5 Fatty Acid Desaturase; Diet, High-Fat; Energy Metabolism; Enzyme Inhibitors; Fatty Acid Desaturases; Gene Expression; Hep G2 Cells; Humans; Inflammation; Insulin Resistance; Leptin; Macrophages; Male; Mice, Inbred C57BL; Obesity; Pyrimidinones; Pyrrolidinones; Reverse Transcriptase Polymerase Chain Reaction; Weight Loss

Macrophages, owning tremendous phenotypic plasticity and diverse functions, were becoming the target cells in various inflammatory, metabolic and immune diseases. Cytochrome P450 epoxygenase 2J2 (CYP2J2) metabolizes arachidonic acid to form epoxyeicosatrienoic acids (EETs), which possess various beneficial effects on cardiovascular system. In the present study, we evaluated the effects of EETs treatment on macrophage polarization and recombinant adeno-associated virus (rAAV)-mediated CYP2J2 expression on lipopolysaccharide (LPS)-induced cardiac dysfunction, and sought to investigate the underlying mechanisms. In vitro studies showed that EETs (1µmol/L) significantly inhibited LPS-induced M1 macrophage polarization and diminished the proinflammatory cytokines at transcriptional and post-transcriptional level; meanwhile it preserved M2 macrophage related molecules expression and upregulated anti-inflammatory cytokine IL-10. Furthermore, EETs down-regulated NF-κB activation and up-regulated peroxisome proliferator-activated receptors (PPARα/γ) and heme oxygenase 1 (HO-1) expression, which play important roles in regulating M1 and M2 polarization. In addition, LPS treatment in mice induced cardiac dysfunction, heart tissue damage and infiltration of M1 macrophages, as well as the increase of inflammatory cytokines in serum and heart tissue, but rAAV-mediated CYP2J2 expression increased EETs generation in heart and significantly attenuated the LPS-induced harmful effects, which mechanisms were similar as the in vitro study. Taken together, the results indicate that CYP2J2/EETs regulates macrophage polarization by attenuating NF-κB signaling pathway via PPARα/γ and HO-1 activation and its potential use in treatment of inflammatory diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cell Polarity; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Gene Expression Regulation; Heme Oxygenase-1; Inflammation; Lipopolysaccharides; Macrophages; Mice; Myocardium; NF-kappa B; PPAR alpha; PPAR gamma; Signal Transduction

Sodium metabisulfite is commonly used as preservative in foods but can oxidize to sulfite radicals initiating molecular oxidation. Ghrelin is a peptide hormone primarily produced in the stomach and has anti-inflammatory effects in many organs. This study aimed to assess endogenous omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) in rat peripheral organs following sodium metabisulfite treatment and determine the possible effect of ghrelin on changes in n-6 inflammatory pathway.. Male Wistar rats included in the study were allowed free access to standard rat chow. Sodium metabisulfite was given by gastric gavage and ghrelin was administered intraperitoneally for 5 weeks. Levels of arachidonic acid (AA, C20:4n-6), dihomo-gamma-linolenic acid (DGLA, C20:3n-6), eicosapentaenoic acid (EPA, C20:5n-3) and docosahexaenoic acid (DHA, C22:6n-3) in liver, heart and kidney tissues were determined by an optimized multiple reaction monitoring (MRM) method using ultra fast-liquid chromatography (UFLC) coupled with tandem mass spectrometry (MS/MS). Cyclooxygenase (COX) and prostaglandin E2 (PGE2) were measured in tissue samples to evaluate changes in n-6 inflammatory pathway.. Omega-6 PUFA levels, AA/DHA and AA/EPA ratio were significantly increased in liver tissue following sodium metabisulfite treatment compared to controls. No significant change was observed in heart and kidney PUFA levels. Tissue activity of COX and PGE2 levels were also significantly increased in liver tissue of sodium metabisulfite treated rats compared to controls. Ghrelin treatment decreased n-6 PUFA levels and reduced COX and PGE2 levels in liver tissue of sodium metabisulfite treated rats.. Current results suggest that ghrelin exerts anti-inflammatory action through modulation of n-6 PUFA levels in hepatic tissue.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonic Acid; Dinoprostone; Docosahexaenoic Acids; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Omega-6; Ghrelin; Inflammation; Kidney; Liver; Male; Myocardium; Prostaglandin-Endoperoxide Synthases; Rats; Rats, Wistar; Spectrometry, Mass, Electrospray Ionization; Sulfites

Cytochrome P-450 epoxygenase (EPOX)-derived epoxyeicosatrienoic acids (EETs), 5-lipoxygenase (5-LO), and leukotriene B4 (LTB4), the product of 5-LO, all play a pivotal role in the vascular inflammatory process. We have previously shown that EETs can alleviate oxidized low-density lipoprotein (ox-LDL)-induced endothelial inflammation in primary rat pulmonary artery endothelial cells (RPAECs). Here, we investigated whether ox-LDL can promote LTB4 production through the 5-LO pathway. We further explored how exogenous EETs influence ox-LDL-induced LTB4 production and activity. We found that treatment with ox-LDL increased the production of LTB4 and further led to the expression and release of both monocyte chemoattractant protein-1 (MCP-1/CCL2) and intercellular adhesion molecule-1 (ICAM-1). All of the above ox-LDL-induced changes were attenuated by the presence of 11,12-EET and 14,15-EET, as these molecules inhibited the 5-LO pathway. Furthermore, the LTB4 receptor 1 (BLT1 receptor) antagonist U75302 attenuated ox-LDL-induced ICAM-1 and MCP-1/CCL2 expression and production, whereas LY255283, a LTB4 receptor 2 (BLT2 receptor) antagonist, produced no such effects. Moreover, in RPAECs, we demonstrated that the increased expression of 5-LO and BLT1 following ox-LDL treatment resulted from the activation of nuclear factor-κB (NF-κB) via the p38 mitogen-activated protein kinase (MAPK) pathway. Our results indicated that EETs suppress ox-LDL-induced LTB4 production and subsequent inflammatory responses by downregulating the 5-LO/BLT1 receptor pathway, in which p38 MAPK phosphorylation activates NF-κB. These results suggest that the metabolism of arachidonic acid via the 5-LO and EPOX pathways may present a mutual constraint on the physiological regulation of vascular endothelial cells.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 5-Lipoxygenase; Blotting, Western; Cells, Cultured; Inflammation; Leukotriene B4; Lipoproteins, LDL; Male; p38 Mitogen-Activated Protein Kinases; Phosphorylation; Pulmonary Artery; Rats; Rats, Sprague-Dawley; Real-Time Polymerase Chain Reaction; Receptors, Leukotriene B4; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Vasodilator Agents

Oxidized low-density lipoprotein (Ox-LDL) is associated with atherosclerotic events through the modulation of arachidonic acid (AA) metabolism and activation of inflammatory signaling. Cytochrome P450 (CYP) epoxygenase-derived epoxyeicosatrienoic acids (EETs) mitigate inflammation through nuclear factor-κB (NF-κB). In this study, we explored the effects and mechanisms of exogenous EETs on the ox-LDL-induced inflammation of pulmonary artery endothelial cells (PAECs), which were cultured from rat pulmonary arteries. We determined that pre-treatment with 11,12-EET or 14,15-EET attenuated the ox-LDL-induced expression and release of intercellular adhesion molecule-1 (ICAM-1), E-selectin, and monocyte chemoattractant protein-1 (MCP-1) in a concentration-dependent manner. In addition, the ox-LDL-induced expression of CYP2J4 was upregulated by 11,12-EET and 14,15-EET (1μM). Furthermore, the endothelial receptor of lectin-like oxidized low-density lipoprotein (LOX-1) was downregulated in PAECs treated with EETs. The inflammatory responses evoked by ox-LDL (100μg/mL) were blocked by pharmacological inhibitors of Erk1/2 mitogen-activated protein kinase (MAPK) (U0126), p38 MAPK (SB203580), and NF-κB (PDTC). In addition, we confirmed that 11,12-EET suppresses phosphorylation of p38, degradation of IκBα, and activation of NF-κB (p65), whereas 14,15-EET can significantly suppress the phosphorylation of p38 and Erk1/2. Our results indicate that EETs exert beneficial effects on ox-LDL-induced inflammation primarily through the inhibition of LOX-1 receptor upregulation, MAPK phosphorylation, and NF-κB activation and through the upregulation of CYP2J4 expression. This study helps focus the current understanding of the contribution of EETs to the regulation of the inflammation of pulmonary vascular endothelial cells. Furthermore, the therapeutic potential of targeting the EET pathway in pulmonary vascular disease will be highlighted.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Anti-Inflammatory Agents; Cells, Cultured; Cytochrome P-450 Enzyme System; Cytochrome P450 Family 2; Dose-Response Relationship, Drug; Endothelial Cells; Enzyme Activation; Inflammation; Inflammation Mediators; Lipoproteins, LDL; Male; Mitogen-Activated Protein Kinases; NF-kappa B; Phosphorylation; Pulmonary Artery; Rats, Sprague-Dawley; RNA, Messenger; Scavenger Receptors, Class E; Signal Transduction

Epoxyeicosatrienoic acids (EETs) are generated from arachidonic acid catalysed by cytochrome P450 (CYP) epoxygenases. In addition to regulating vascular tone EETs may alleviate inflammation and ROS. The present study was conducted to determine whether CYP2C8 gene overexpression was able to increase the level of EETs, and subsequently prevent TNF-α induced inflammation and reactive oxygen species (ROS) in human umbilical vein endothelial cells (HUVECs) and macrophages. Peroxisome proliferator‑activated receptor γ (PPARγ) activation, nuclear factor-κB (NF-κB) activation, endothelial nitric oxide synthase (eNOS) activation, gp-91 activation, and inflammatory cytokine expression were detected by western blot analysis or enzyme-linked immuno-sorbent assay. Intracellular reactive oxygen species (ROS) was measured by flow cytometry, while the migration of vascular smooth muscle cells (VSMCs) was detected by transwell assay. pCMV-mediated CYP2C8 overexpression and its metabolites, EETs, markedly suppressed TNF-α induced inflammatory cytokines IL-6 and MCP-1 expression via the activation of NF-κB and degradation of IκBα. Moreover, pretreatment with 11,12-EET significantly blocked TNF-α-induced ROS production. CYP2C8‑derived EETs also effectively alleviated the migration of VSMCs and improved the function of endothelial cells through the upregulation of eNOS, which was significantly decreased under the stimulation of TNF-α. Furthermore, these protective effects observed were mediated by PPARγ activation. To the best of our knowledge, the results of the present study demonstrated for the first time that CYP2C8-derived EETs exerted antivascular inflammatory and anti-oxidative effects, at least in part, through the activation of PPARγ. Thus, the CYP2C8 gene may be useful in the prevention and treatment of vascular inflammatory diseases.

Topics: 8,11,14-Eicosatrienoic Acid; Cell Movement; Chemokine CCL2; Cytochrome P-450 CYP2C8; Human Umbilical Vein Endothelial Cells; Humans; Inflammation; Interleukin-6; Intracellular Space; Macrophages; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; NF-kappa B; Nitric Oxide Synthase Type III; PPAR gamma; Reactive Oxygen Species; Transfection; Tumor Necrosis Factor-alpha; Up-Regulation

Dietary supplementation with botanical oils that contain n-6 and n-3 eighteen carbon chain (18C)-PUFA such as γ linolenic acid (GLA, 18:3n-6), stearidonic acid (SDA, 18:4n-3) and α linolenic acid (ALA, 18:3n-3) have been shown to impact PUFA metabolism, alter inflammatory processes including arachidonic acid (AA) metabolism and improve inflammatory disorders.. The diet of mild asthmatics patients was supplemented for three weeks with varying doses of two botanical seed oils (borage oil [Borago officinalis, BO] and echium seed oil [Echium plantagineum; EO]) that contain SDA, ALA and GLA. A three week wash out period followed. The impact of these dietary manipulations was evaluated for several biochemical endpoints, including in vivo PUFA metabolism and ex vivo leukotriene generation from stimulated leukocytes.. Supplementation with several EO/BO combinations increased circulating 20-22 carbon (20-22C) PUFAs, including eicosapentaenoic acid (EPA), docosapentaenoic acid (DPA), and dihommo-gammalinolenic acid (DGLA), which have been shown to inhibit AA metabolism and inflammation without impacting circulating AA levels. BO/EO combinations also inhibited ex vivo leukotriene generation with some combinations attenuating cysteinyl leukotriene generation in stimulated basophils by >50% and in stimulated neutrophils by >35%.. This study shows that dietary supplementation with BO/EO alters 20-22C PUFA levels and attenuates leukotriene production in a manner consistent with a reduction in inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Adolescent; Adult; alpha-Linolenic Acid; Asthma; Cells, Cultured; Dietary Supplements; Echium; Eicosapentaenoic Acid; Fatty Acids, Omega-3; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Inflammation; Leukocytes, Mononuclear; Leukotrienes; Male; Middle Aged; Plant Oils; Seeds

Acute pulmonary infection by Streptococcus pneumoniae is characterized by high bacterial numbers in the lung, a robust alveolar influx of polymorphonuclear cells (PMNs), and a risk of systemic spread of the bacterium. We investigated host mediators of S. pneumoniae-induced PMN migration and the role of inflammation in septicemia following pneumococcal lung infection. Hepoxilin A3 (HXA3) is a PMN chemoattractant and a metabolite of the 12-lipoxygenase (12-LOX) pathway. We observed that S. pneumoniae infection induced the production of 12-LOX in cultured pulmonary epithelium and in the lungs of infected mice. Inhibition of the 12-LOX pathway prevented pathogen-induced PMN transepithelial migration in vitro and dramatically reduced lung inflammation upon high-dose pulmonary challenge with S. pneumoniae in vivo, thus implicating HXA3 in pneumococcus-induced pulmonary inflammation. PMN basolateral-to-apical transmigration in vitro significantly increased apical-to-basolateral transepithelial migration of bacteria. Mice suppressed in the expression of 12-LOX exhibited little or no bacteremia and survived an otherwise lethal pulmonary challenge. Our data suggest that pneumococcal pulmonary inflammation is required for high-level bacteremia and systemic infection, partly by disrupting lung epithelium through 12-LOX-dependent HXA3 production and subsequent PMN transepithelial migration.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 12-Lipoxygenase; Bacillus subtilis; Bacteremia; Cell Line, Tumor; Cell Movement; Chemotactic Factors; Humans; Inflammation; Lung; Lung Diseases; Mice; Mice, Inbred C57BL; Mice, Knockout; Neutrophils; Pneumococcal Infections; Streptococcus pneumoniae; Transendothelial and Transepithelial Migration

14,15-Epoxyeicosatrienoic acids (14,15-EETs) generated from arachidonic acid by cytochrome P450 epoxygenases have beneficial effects in certain cardiovascular diseases, and increased 14,15-EET levels protect the cardiovascular system. 14,15-EETs are rapidly hydrolyzed by soluble epoxide hydrolase (sEH) to the corresponding 14,15-dihydroxyeicosatrienoic acids (14,15-DHETs), which are generally less biologically active but more stable metabolite. A functionally relevant polymorphism of the CYP2J2 gene is independently associated with an increased risk of coronary heart disease (CHD), and the major CYP2J2 product is 14,15-EETs. 14,15-DHETs can be considered a relevant marker of CYP2J2 activity. Therefore, the aim of the present study was to evaluate the plasma 14,15-DHET levels to reflect the 14,15-EET levels in an indirectly way in patients with CHD, and to highlight the growing body of evidence that 14,15-EETs also play a role in anti-inflammatory and lipid-regulating effects in patients with CHD. This was achieved by investigating the relationship between 14,15-DHETs and high-sensitivity C-reactive protein (hs-CRP) and blood lipoproteins.. Samples of peripheral venous blood were drawn from 60 patients with CHD and 60 healthy controls. A 14,15-DHET enzyme-linked immunosorbent assay kit (14,15-DHET ELISA kit) was used to measure the plasma 14,15-DHET levels. Hs-CRP, total cholesterol, triglyceride, high-density lipoprotein cholesterol, and low-density lipoprotein-cholesterol levels were measured.. 14,15-DHET levels (2.53 ± 1.60 ng/mL) were significantly higher in patients with CHD as compared with those of the healthy controls (1.65 ± 1.54 ng/mL, P < 0.05). There was a significant positive correlation between 14,15-DHETs and hs-CRP levels (R = 0.286, P = 0.027). However, there was no significant correlation between 14,15-DHETs and blood lipoproteins (all, P > 0.05).. Increased plasma 14,15-DHET levels reflect the decreased of 14,15-EET levels in an indirectly way. Indicated that decreased plasma 14,15-EET levels might be involved in the inflammatory reaction process in atherosclerosis.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; C-Reactive Protein; Case-Control Studies; Cholesterol, HDL; Cholesterol, LDL; Coronary Disease; Cytochrome P-450 CYP2J2; Cytochrome P-450 Enzyme System; Female; Humans; Inflammation; Male; Middle Aged; Statistics, Nonparametric; Triglycerides

It has been recognized that certain long-chain polyunsaturated fatty acids (LC-PUFAs) are involved in inflammation and its resolution. It has also been shown that ethnicity may be a factor in affecting systemic inflammation, and limited evidence suggests it may influence plasma LC-PUFA composition. Given the links among these three factors, we aim to determine ethnicity-based differences in plasma LC-PUFA composition among White, Black, Hispanic and Chinese participants, and whether such differences contribute to variations in markers of inflammation and endothelial activation in a sub-cohort of the Multi-Ethnic Study of Atherosclerosis (MESA).. Plasma phospholipid LC-PUFAs levels (%) were determined in 2848 MESA participants using gas chromatography-flame ionization detection. Enzyme immunoassays determined inflammatory markers levels for high-sensitivity C-reactive protein (n=2848), interleukin-6 (n=2796), soluble tumor necrosis factor-α receptor type 1 (n=998), and endothelial activation markers soluble intercellular adhesion molecule-1 (n=1192) and soluble E-selectin (n=998). The modifying influence of ethnicity was tested by linear regression analysis.. Chinese adults were found to have the highest mean levels of plasma eicosapentaenoic acid (EPA, 1.24%) and docosahexaenoic acid (DHA, 4.95%), and the lowest mean levels of γ-linolenic (0.10%), dihomo-γ-linolenic (DGLA, 2.96%) and arachidonic (10.72%) acids compared with the other ethnicities (all P ≤ 0.01). In contrast, Hispanics had the lowest mean levels of plasma EPA (0.70%) and DHA (3.49%), and the highest levels of DGLA (3.59%; all P ≤ 0.01). Significant differences in EPA and DHA among ethnicities were attenuated following adjustment for dietary non-fried fish and fish oil supplementation. Ethnicity did not modify the associations of LC-PUFAs with markers of inflammation or endothelial activation (all P (interaction)>0.05).. The absence of a modifying effect of ethnicity indicates that the putative benefits of LC-PUFAs with respect to inflammation are pan-ethnic. Future longitudinal studies may elucidate the origin(s) of ethnicity-based differences in LC-PUFA composition and whether certain patterns, that is, high plasma levels of DGLA and low levels of EPA/DHA, contribute to inflammation-associated health outcomes.

Topics: 8,11,14-Eicosatrienoic Acid; Aged; Arachidonic Acid; Asian People; Atherosclerosis; Biomarkers; Diet; Dietary Fats; Dietary Supplements; Docosahexaenoic Acids; Eicosapentaenoic Acid; Endothelium, Vascular; Fatty Acids, Unsaturated; Female; Humans; Inflammation; Linear Models; Male; Middle Aged; Nutritional Status; Phospholipids

Peripheral inflammation initiates changes in spinal nociceptive processing leading to hyperalgesia. Previously, we demonstrated that among 102 lipid species detected by LC-MS/MS analysis in rat spinal cord, the most notable increases that occur after intraplantar carrageenan are metabolites of 12-lipoxygenases (12-LOX), particularly hepoxilins (HXA(3) and HXB(3)). Thus, we examined involvement of spinal LOX enzymes in inflammatory hyperalgesia. In the current work, we found that intrathecal (IT) delivery of the LOX inhibitor nordihydroguaiaretic acid prevented the carrageenan-evoked increase in spinal HXB(3) at doses that attenuated the associated hyperalgesia. Furthermore, IT delivery of inhibitors targeting 12-LOX (CDC, Baicalein), but not 5-LOX (Zileuton) dose-dependently attenuated tactile allodynia. Similarly, IT delivery of 12-LOX metabolites of arachidonic acid 12(S)-HpETE, 12(S)-HETE, HXA(3), or HXB(3) evoked profound, persistent tactile allodynia, but 12(S)-HpETE and HXA(3) produced relatively modest, transient heat hyperalgesia. The pronociceptive effect of HXA(3) correlated with enhanced release of Substance P from primary sensory afferents. Importantly, HXA(3) triggered sustained mobilization of calcium in cells stably overexpressing TRPV1 or TRPA1 receptors and in acutely dissociated rodent sensory neurons. Constitutive deletion or antagonists of TRPV1 (AMG9810) or TRPA1 (HC030031) attenuated this action. Furthermore, pretreatment with antihyperalgesic doses of AMG9810 or HC030031 reduced spinal HXA(3)-evoked allodynia. These data indicate that spinal HXA(3) is increased by peripheral inflammation and promotes initiation of facilitated nociceptive processing through direct activation of TRPV1 and TRPA1 at central terminals.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 12-Lipoxygenase; Hyperalgesia; Inflammation; Mice; Spinal Cord; Transient Receptor Potential Channels; TRPA1 Cation Channel; TRPV Cation Channels

Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.. In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH(-/-) mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH(-/-) mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.. Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Blotting, Western; Calcitonin Gene-Related Peptide; Calcium; Cells, Cultured; Chromatography, Liquid; Epoxide Hydrolases; Ganglia, Spinal; Hyperalgesia; Immunohistochemistry; Inflammation; Mice; Mice, Inbred C57BL; Mice, Knockout; Tandem Mass Spectrometry; Transient Receptor Potential Channels; TRPA1 Cation Channel

The widespread use of statins for hypercholesterolemia has uncovered pleiotropic anti-inflammatory properties that were unexpected based on the drugs' original design; yet, mechanisms for these protective actions remain uncertain. In this study lovastatin triggered biosynthesis of the anti-inflammatory and pro-resolving mediator 15-epi-lipoxin A(4) (15-epi-LXA(4)). During interactions between human neutrophils and airway epithelial cells, the statin-induced increase in 15-epi-LXA(4) was associated with increased 14,15-epoxyeicosatrienoic acid (14,15-EET) generation. When added to activated neutrophils, 14,15-EET enhanced 15-epi-LXA(4) biosynthesis. In a murine model of airway mucosal injury and inflammation, lovastatin increased 15-epi-LXA(4) formation in vivo and markedly decreased acute lung inflammation. Administration of 15-epi-LXA(4) also inhibited lung inflammation in an additive manner with lovastatin. Together, these results indicate that statin-triggered 15-epi-LXA(4) generation during human leukocyte-airway epithelial cell interactions is an endogenous mechanism for statin-mediated tissue protection at mucosal surfaces that may also be relevant in the statins' ability to stimulate the resolution of inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Acute Disease; Animals; Anticholesteremic Agents; Cell Line; Disease Models, Animal; Female; Humans; Hypercholesterolemia; Inflammation; Inflammation Mediators; Lipoxins; Lovastatin; Male; Mice; Neutrophils; Pneumonia; Respiratory Mucosa

Angiotensin II type 2 (AT(2)) receptors can be regarded as an endogenous repair system, because the AT(2) receptor is upregulated in tissue damage and mediates tissue protection. A potential therapeutic use of this system has only recently come within reach through synthesis of the first selective, orally active, nonpeptide AT(2) receptor agonist, compound 21 (C21; dissociation constant for AT(2) receptor: 0.4 nM; dissociation constant for angiotensin II type 1 receptor: >10,000 nM). This study tested AT(2) receptor stimulation with C21 as a potential future therapeutic approach for the inhibition of proinflammatory cytokines and of nuclear factor kappaB. C21 dose-dependently (1 nM to 1 micromol/L) reduced tumor necrosis factor-alpha-induced interleukin 6 levels in primary human and murine dermal fibroblasts. AT(2) receptor specificity was controlled for by inhibition with the AT(2) receptor antagonist PD123319 and by the absence of effects in AT(2) receptor-deficient cells. AT(2) receptor-coupled signaling leading to reduced interleukin 6 levels involved inhibition of nuclear factor kappaB, activation of protein phosphatases, and synthesis of epoxyeicosatrienoic acid. Inhibition of interleukin 6 promoter activity by C21 was comparable in strength to inhibition by hydrocortisone. C21 also reduced monocyte chemoattractant protein 1 and tumor necrosis factor-alpha in vitro and in bleomycin-induced toxic cutaneous inflammation in vivo. This study is the first to show the anti-inflammatory effects of direct AT(2) receptor stimulation in vitro and in vivo by the orally active, nonpeptide AT(2) receptor agonist C21. These data suggest that pharmacological AT(2) receptor stimulation may be an orally applicable future therapeutic approach in pathological settings requiring the reduction of interleukin 6 or inhibition of nuclear factor kappaB.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Cell Nucleus; Cells, Cultured; Chemokine CCL2; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Female; Fibroblasts; Humans; Inflammation; Interleukin-6; Mice; NF-kappa B; Receptor, Angiotensin, Type 2; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Signal Transduction; Sulfonamides; Thiophenes; Tumor Necrosis Factor-alpha

Neutrophil transmigration across mucosal surfaces contributes to dysfunction of epithelial barrier properties, a characteristic underlying many mucosal inflammatory diseases. Thus, insight into the directional movement of neutrophils across epithelial barriers will provide important information relating to the mechanisms of such inflammatory disorders. The eicosanoid hepoxilin A(3), an endogenous product of 12-lipoxygenase activity, is secreted from the apical surface of the epithelial barrier and establishes a chemotactic gradient to guide neutrophils from the submucosa across epithelia to the luminal site of an inflammatory stimulus, the final step in neutrophil recruitment. Currently, little is known regarding how hepoxilin A(3) is secreted from the intestinal epithelium during an inflammatory insult. In this study, we reveal that hepoxilin A(3) is a substrate for the apical efflux ATP-binding protein transporter multidrug resistance-associated protein 2 (MRP2). Moreover, using multiple in vitro and in vivo models, we show that induction of intestinal inflammation profoundly up-regulates apical expression of MRP2, and that interfering with hepoxilin A(3) synthesis and/or inhibition of MRP2 function results in a marked reduction in inflammation and severity of disease. Lastly, examination of inflamed intestinal epithelia in human biopsies revealed up-regulation of MRP2. Thus, blocking hepoxilin A(3) synthesis and/or inhibiting MRP2 may lead to the development of new therapeutic strategies for the treatment of epithelial-associated inflammatory conditions.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 12-Lipoxygenase; Gene Expression Regulation; Humans; Inflammation; Intestinal Diseases; Intestinal Mucosa; Mice; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Neutrophil Infiltration; Neutrophils

Cyclooxygenase and lipoxygenase metabolism of arachidonic acid produces compounds important in cardiovascular control. Further, arachidonic acid can be metabolised by cytochrome p450 to produce epoxyeicosatrienoic acids (EETs). These derivatives are inactivated by soluble epoxide hydrolase (sEH). The potential role of these EETs in hypertension and cardiac remodelling has been determined using the selective sEH inhibitor, N-adamantyl-N'-dodecylurea (ADU), in deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Experiments were performed on male Wistar rats following uninephrectomy alone (UNX rats) or uninephrectomy with administration of DOCA (25 mg every fourth day subcutaneously) and 1% NaCl in drinking water (DOCA-salt rats). ADU (10 mg/kg/d subcutaneously) was administered for 2 wk starting 2 wk after surgery. Cardiovascular structure and function were determined using organ wet weights, histological analysis of collagen and inflammation, isolated heart and thoracic aortic ring preparations, and electrophysiological measurements. DOCA-salt hypertensive rats developed hypertension, hypertrophy, perivascular and interstitial fibrosis, endothelial dysfunction, and prolongation of the cardiac action potential duration within 4 wk. Administration of ADU prevented the further increase in systolic blood pressure and left-ventricular wet weight and normalized endothelial function. ADU treatment did not change inflammatory cell infiltration, collagen deposition, or cardiac action potential duration. EETs may be involved in the development of hypertension and endothelial dysfunction in DOCA-salt rats, but not in excessive collagen deposition or electrophysiological abnormalities.

Topics: 8,11,14-Eicosatrienoic Acid; Animals; Aorta, Thoracic; Desoxycorticosterone; Electrophysiology; Endothelium, Vascular; Enzyme Inhibitors; Epoxide Hydrolases; Heart Ventricles; Hypertension; Inflammation; Male; Rats; Rats, Wistar; Salts

The mechanism by which neutrophils [polymorphonuclear leukocyte (PMNs)] are stimulated to move across epithelial barriers at mucosal surfaces has been basically unknown in biology. IL-8 has been shown to stimulate PMNs to leave the bloodstream at a local site of mucosal inflammation, but the chemical gradient used by PMNs to move between adjacent epithelial cells and traverse the tight junction at the apical neck of these mucosal barriers has eluded identification. Our studies not only identify this factor, previously termed pathogen-elicited epithelial chemoattractant, as the eicosanoid hepoxilin A(3) (hepA(3)) but also demonstrate that it is a key factor promoting the final step in PMN recruitment to sites of mucosal inflammation. We show that hepA(3) is synthesized by epithelial cells and secreted from their apical surface in response to conditions that stimulate inflammatory events. Our data further establish that hepA(3) acts to draw PMNs, via the establishment of a gradient across the epithelial tight junction complex. The functional significance of hepA(3) to target PMNs to the lumen of the gut at sites of inflammation was demonstrated by the finding that disruption of the 12-lipoxygenase pathway (required for hepA(3) production) could dramatically reduce PMN-mediated tissue trauma, demonstrating that hepA(3) is a key regulator of mucosal inflammation.

Topics: 8,11,14-Eicosatrienoic Acid; Humans; Inflammation; Intestinal Mucosa; Neutrophils; Salmonella typhimurium

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 8,11,14-Eicosatrienoic Acid; Animals; Burns; Contact Lenses; Cytochrome P-450 Enzyme System; Disease Models, Animal; Eicosanoids; Eye Injuries; Inflammation; Neovascularization, Physiologic; Rabbits; Wound Healing

In this study we set out to investigate whether the inflammatory agents, bradykinin (BK) and platelet activating factor (PAF), affect the lipoxygenase pathway in rat skin in vivo and whether the main products so formed may be involved in the inflammatory actions of these agents. In vitro preparations of epidermis were also investigated to determine whether lipoxygenases are stimulated by these agents. We also investigated the actions of arachidonic acid and 12(S)-HPETE as substrates for the lipoxygenases. Our results indicated that 12-lipoxygenase is actively and selectively stimulated in a dose-dependent way in both preparations by the administration of BK and PAF; the main product, 12-HETE, was shown by chiral analysis to be exclusively of the S-configuration, indicating that 12(S)-lipoxygenase was present in the rat skin and was stimulated by these inflammatory agents. Hepoxilins were also formed but to a lesser extent in both in vivo and in vitro preparations. In separate experiments, 12(S)-HETE administered intradermally on its own (40 ng/site), increased vascular permeability as also seen with bradykinin (100 ng/site) and PAF (10 ng/site). However, unlike previously observed with hepoxilin A3 administration, 12(S)-HETE did not stimulate the action of BK on vascular permeability, suggesting that the two compounds may have different mechanisms of action to enhance inflammation. These observations suggest that the vascular permeability and plasma extravasation observed with both inflammatory agents (BK and PAF) may be mediated at least in part through the activation of 12(S)-lipoxygenase, resulting in enhanced formation of 12(S)-HETE which causes acute inflammation.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 8,11,14-Eicosatrienoic Acid; Animals; Arachidonate 12-Lipoxygenase; Bradykinin; Capillary Permeability; Enzyme Activation; Inflammation; Inflammation Mediators; Male; Platelet Activating Factor; Rats; Rats, Wistar; Skin

The corneal epithelium metabolizes arachidonic acid by a cytochrome P450-(CYP) mediated pathway to 12(R)hydroxy-5,8,10,14-eicosatrienoic acid [12(R)-HETE] and 12(R)hydroxy-5,8,14-eicosatrienoic acid [12(R)-HETrE]. Both metabolites possess potent inflammatory properties with 12(R)-HETrE being a powerful angiogenic factor and assume the role of inflammatory mediators in hypoxia- and chemical-induced injury in the cornea, in vivo. We developed an in vitro model of corneal organ culture to characterize the biochemical and molecular events involved in the increased synthesis of these metabolites. These cultured corneas exhibit epithelial cytochrome P450 CYP-dependent 12(R)-HETE and 12(R)-HETrE synthesis as indicated by chiral analysis and by the ability of CYP enzyme inhibitors to repress their synthesis. Hypoxia greatly and selectively stimulated the synthesis of 12(R)-HETE (7-fold over control normoxic conditions) and 12(R)-HETrE. The bacterial endotoxin, lipopolysaccharide, also increased the synthesis of these eicosanoids, substantiating the notion that this activity may function as an inflammatory pathway. These metabolites were detected in the culture medium by gas chromatography/mass spectroscopy (GC/MS) analysis and their levels significantly increased in hypoxia-treated corneas, further indicating their endogenous formation in response to injury. This in vitro model provides an excellent preparation for studying factors regulating the synthesis of these inflammatory eicosanoids and for isolating, identifying and characterizing the CYP protein responsible for their synthesis.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; 8,11,14-Eicosatrienoic Acid; Animals; Cell Hypoxia; Culture Media; Cytochrome P-450 Enzyme System; Epithelium, Corneal; Inflammation; Lipopolysaccharides; Organ Culture Techniques; Rabbits

Reports that vegetable oils which contain gamma-linolenic acid (18:3n-6) may exert beneficial effects on cutaneous disorders prompted us to investigate whether epidermis possesses the ability to transform dihomogammalinolenic acid (20:3n-6), the epidermal elongase product of 18:3n-6, into oxidative metabolites with anti-inflammatory potential. Incubations of [1-14C]20:3n-6 with the 105,000 g particulate (microsomal) fraction from guinea pig epidermal homogenate resulted in the formation of the 1-series prostaglandin PGE1. The identity of this product was confirmed by argentation thin-layer chromatography (TLC), reverse phase-HPLC, and conversion with alkali treatment to PGB1. Incubations of [1-14C]20:3n-6 with the 105,000 g supernatant (cytosolic) fraction from guinea pig epidermal homogenate resulted in the formation of the 15-lipoxygenase product 15-hydroxy-8, 11, 13-eicosatrienoic acid (15-OH-20:3n6). The identity of this product was confirmed by normal phase-HPLC and gas chromatography/mass spectrometry (GC/MS). Thus, data from these studies indicate the capacity of enzymes in the microsomal and cytosolic fractions of guinea pig epidermal homogenates to transform 20:3n-6 to the eicosanoids PGE1 and 15-OH 20:3n-6, products which reportedly have anti-inflammatory properties. The in vivo significance of these findings remains to be explored.

Topics: 8,11,14-Eicosatrienoic Acid; Alprostadil; Animals; Arachidonate 12-Lipoxygenase; Arachidonate 5-Lipoxygenase; Blood Platelets; Chromatography, High Pressure Liquid; Epidermis; Fatty Acids, Unsaturated; Gas Chromatography-Mass Spectrometry; Guinea Pigs; Humans; Hydroxyeicosatetraenoic Acids; Inflammation; Male; Oxidation-Reduction; Prostaglandin-Endoperoxide Synthases; Prostaglandins B; Rats

Topics: 8,11,14-Eicosatrienoic Acid; Arachidonic Acids; Blood Platelets; Colchicine; Feedback; Humans; Immunity; Inflammation; Melatonin; Prostaglandins; Prostaglandins E; Thromboxane A2