5-hydroxy-6-8-11-14-eicosatetraenoic-acid and Arthritis--Rheumatoid

A lipid-rich extract, prepared by supercritical fluid (CO2) extraction of freeze-dried stabilized NZ green-lipped mussel powder (Lyprinol) has shown significant anti-inflammatory (AI) activity when given to animals and humans. When treated p.o. with Lyprinol, Wistar and Dark Agouti rats developed neither adjuvant-induced polyarthritis or collagen(II)-induced auto-allergic arthritis. This was achieved with doses < NSAIDs, and 200 times < of other seed or fish oils. Lyprinol subfractions inhibited LTB4 biosynthesis by PMN in vitro, and PGE2 production by activated macrophages. Much of this AI activity was associated with omega-3 PUFAs and natural antioxidants [e.g. carotenoids]. In contrast to NSAIDs, Lyprinol is non-gastro toxic in disease-stressed rats at 300 mg/kg p.o., and does not affect platelet aggregation [human, rat]. Clinical studies, either controlled or randomized, have demonstrated very significant AI activity in patients with osteoarthritis (OA), rheumatoid arthritis (RA), asthma, and other inflammatory conditions. Lyprinol is a reproducible, stable source of bioactive lipids with much greater potency than plant/marine oils currently used as nutritional supplements to ameliorate signs of inflammation.

Topics: Animals; Anti-Asthmatic Agents; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Experimental; Arthritis, Rheumatoid; Asthma; Bivalvia; Clinical Trials as Topic; Double-Blind Method; Drug Administration Routes; Drug Evaluation, Preclinical; Drug Stability; Freeze Drying; Humans; Hydroxyeicosatetraenoic Acids; Leukotrienes; Lipids; Lipoxygenase Inhibitors; Medicine, Traditional; Neutrophils; New Zealand; Osteoarthritis; Plant Oils; Preservatives, Pharmaceutical; Randomized Controlled Trials as Topic; Rats; Rats, Wistar; Tartrates; Tissue Extracts; Treatment Outcome

To determine the association of polyunsaturated fatty acid (PUFA)-derived lipid mediators with progression from rheumatoid arthritis (RA)-related autoimmunity to inflammatory arthritis (IA).. We conducted a prospective cohort study using data from the Studies of the Etiology of Rheumatoid Arthritis (SERA). SERA enrolled first-degree relatives (FDRs) of individuals with RA (FDR cohort) and individuals who screened positive for RA-related autoantibodies at health fairs (screened cohort). We followed up 133 anti-cyclic citrullinated peptide 3.1 (anti-CCP3.1)-positive participants, 29 of whom developed IA. Lipid mediators selected a priori were quantified from stored plasma samples using liquid chromatography tandem mass spectrometry. We fit multivariable Cox proportional hazards models for each lipid mediator as a time-varying variable. For lipid mediators found to be significantly associated with IA, we then examined interleukin-1β (IL-1β), IL-6, IL-8, and tumor necrosis factor (TNF) as potential statistical mediators.. For every 1 natural log pg/ml increase in the circulating plasma levels of proinflammatory 5-HETE, the risk of developing IA increased by 241% (hazard ratio 2.41 [95% confidence interval 1.43-4.07]) after adjusting for age at baseline, cohort (FDR or screened), and shared epitope status. The models examining 15-HETE and 17-HDHA had the same trend but did not reach significance. We did not find evidence that the association between 5-HETE and IA risk was influenced by the proinflammatory cytokines tested.. In a prospective cohort of anti-CCP-positive individuals, higher levels of 5-HETE, an important precursor to proinflammatory leukotrienes, is associated with subsequent IA. Our findings highlight the potential significance of these PUFA metabolites in pre-RA populations.

Topics: Adult; Aged; Anti-Citrullinated Protein Antibodies; Arthritis, Rheumatoid; Autoimmunity; Cohort Studies; Disease Progression; Docosahexaenoic Acids; Family; Fatty Acids, Unsaturated; Female; Humans; Hydroxyeicosatetraenoic Acids; Incidence; Interleukin-1beta; Interleukin-6; Interleukin-8; Male; Mediation Analysis; Middle Aged; Multivariate Analysis; Proportional Hazards Models; Prospective Studies; Tumor Necrosis Factor-alpha

The inhibition of 5-lipoxygenase could be involved in the mechanism of action of methotrexate (MTX). We studied 8 patients with active rheumatoid arthritis (RA) immediately before and the day after the first dose of MTX (10 mg intramuscularly). Leukotriene B4 (LTB4) formation by polymorphonuclear leukocytes was significantly decreased (32%, p less than 0.01). This essentially involved released LTB4. A slight decrease was also obtained in omega-oxidation products. Similar results were obtained for plasma LTB4 (30%, p less than 0.02). A non-significant decrease in 5-HETE was noted. Conversely, 12-HETE was not modified. Our results suggest MTX has an effect on the 5-lipoxygenase pathway, particularly at the LTA4 epoxide hydrolase step, since 5-HETE and 6-trans-LTB4 isomers are not involved.

Topics: 12-Hydroxy-5,8,10,14-eicosatetraenoic Acid; Arachidonate 12-Lipoxygenase; Arachidonate 5-Lipoxygenase; Arachidonic Acids; Arthritis, Rheumatoid; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Female; Humans; Hydroxyeicosatetraenoic Acids; Injections, Intramuscular; Leukotriene B4; Male; Methotrexate; Middle Aged; Neutrophils; Time Factors

We studied the effects of a single, oral dose of methotrexate (MTX) on arachidonic acid metabolism in neutrophils from 6 patients with rheumatoid arthritis, which were obtained 1 day before and 1 day after their usual weekly MTX dose. The 6 patients had received a mean weekly MTX dose of 9.6 mg (range 5-15) for a mean of 61.7 months (range 58-64), and none received concomitant corticosteroids. Total generation of leukotriene B4 (LTB4) in neutrophils stimulated ex vivo with 10 microM calcium ionophore A23187 for 20 minutes was significantly suppressed, by a mean of 53%, after the MTX dose compared with the predose levels (mean +/- SEM 13.0 +/- 1.4 ng/10(6) cells versus 6.0 +/- 0.9 ng/10(6) cells; P = 0.0019), reflecting a comparable suppression of both released and cell-retained LTB4. A 49% decrease in omega-oxidation products of LTB4 demonstrates that decreased LTB4 synthesis, rather than increased degradation, is responsible for the decrease in LTB4 generation. The absence of a significant change in either 3H-labeled arachidonic acid release or platelet-activating factor generation indicates that the observed decrease in LTB4 synthesis was apparently not caused by diminished phospholipase A2 activity. A 28% decrease in the total formation of the 5-lipoxygenase products 5-hydroxyeicosatetraenoic acid and the 6-trans-LTB4 diastereoisomers, and a 48% suppression of production of LTB4 plus its omega-oxidation metabolites after the MTX dose suggest inhibition of 5-lipoxygenase activity and possible suppression of leukotriene A4 epoxide hydrolase activity.

Topics: Aged; Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Calcimycin; Chemotaxis, Leukocyte; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Methotrexate; Middle Aged; Neutrophils; Phospholipases; Platelet Activating Factor

Circulating human neutrophil granulocytes (PMNs) from patients with rheumatoid arthritis (RA) have earlier been described to possess an enhanced capacity for production of certain 5-lipoxygenase-derived metabolites of arachidonic acid (AA), 5-hydroxyeicosatetraenoic acid (5-HETE) and leukotriene B4 (LTB4). In the present investigation the endogenous AA metabolism of synovial fluid PMNs of RA patients was studied and compared with that of the corresponding circulating PMNs. Synovial fluid PMNs prelabelled with 14C-AA released significantly less radioactivity than circulating PMNs when stimulated with calcium ionophore. Furthermore, synovial fluid PMNs produced significantly smaller amounts of both 5-HETE and LTB4 than circulating PMNs from the same patients, whereas no such difference was observed in the LTB4 catabolites or the cyclo-oxygenase products. More information dealing with the complex way in which arachidonic acid is metabolized in diseased RA joints may provide future rational approaches in the treatment of this chronic inflammatory disease.

Topics: Adult; Aged; Arachidonic Acids; Arthritis, Rheumatoid; Female; Humans; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Male; Middle Aged; Neutrophils; Synovial Fluid

The formation of 5-lipoxygenase products (5-hydroxyeicosatetraenoic acid [5-HETE], leukotriene B4 [LTB4], and leukotriene C4 [LTC4]) by polymorphonuclear and mononuclear leukocytes isolated from peripheral blood of patients with rheumatoid arthritis was evaluated and compared with the data obtained from a group of control subjects. Although the levels of arachidonic acid metabolites via 5-lipoxygenase pathway by stimulated polymorphonuclear cells were comparable between patients and controls, mononuclear leukocytes from patients synthesized, when stimulated, significantly greater amounts of 5-HETE, LTB4, and LTC4 than did cells isolated from normal subjects. In addition, the release of superoxide anion, stimulated by either a particulate or a soluble stimulus, was increased in mononuclear cells from patients. The enhanced capacity of peripheral mononuclear leukocytes isolated from patients with rheumatoid arthritis to generate proinflammatory metabolites of arachidonic acid and oxygenated species with bactericidal and tissue-damaging properties may contribute to the pathogenesis of this complex disease.

Topics: Arthritis, Rheumatoid; Calcimycin; Cell Aggregation; Humans; Hydroxyeicosatetraenoic Acids; Leukocytes, Mononuclear; Leukotriene B4; N-Formylmethionine Leucyl-Phenylalanine; Neutrophils; Phagocytosis; SRS-A; Superoxides

Topics: Arachidonic Acid; Arachidonic Acids; Arthritis, Rheumatoid; Diclofenac; Dinoprostone; Humans; Hydroxyeicosatetraenoic Acids; Metabolic Clearance Rate; Osteoarthritis; Prostaglandins E; Synovial Fluid; Thromboxane B2

The predominant lipoxygenase products of arachidonic acid were extracted and purified from synovial fluid and sonicates of synovial tissue of patients with rheumatoid arthritis (RA), spondyloarthritis (SA), or a noninflammatory arthropathy (NIA). The concentration of 5(S),12(R)-dihydroxy-6,8,10-(trans/trans/cis)-14-cis-eicosatetraenoic acid (leukotriene B4) in synovial fluid was elevated significantly in patients with RA and a positive latex test for rheumatoid factor (P < 0.05, n = 14) and in patients with SA (P < 0.05, n = 10), compared with that of subjects with NIA (n = 9). The content of 5(S)-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE), but not of leukotriene B4, was elevated significantly in synovial tissue of seven patients with RA in comparison with that of four subjects with NIA (P < 0.05). A single intra-articular injection of corticosteroid significantly lowered the synovial fluid level of leukotriene B4 in six patients with RA. These data suggest an involvement of the potent chemotactic factors 5-HETE and leukotriene B4 in human inflammatory disease.

Topics: Arachidonic Acids; Arthritis, Rheumatoid; Chemotactic Factors; Hydroxyeicosatetraenoic Acids; Leukotriene B4; Lipoxygenase; Neutrophils; Spondylitis, Ankylosing; Synovial Fluid