Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0003873 (rheumatoid arthritis)
 53,068 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

By initial 3H-thymidine labelling an enhanced monocyte proliferation in the bone marrow of patients with rheumatoid arthritis is demonstrated. The significant monocyte proliferation correlates positively with the erythrocyte sedimentation rate but shows a negative correlation with age. The high significance of the mononuclear phagocyte (MNP) system in the pathogenesis of rheumatoid arthritis is seriously underlined by the experimental findings in our allergic arthritis model. Benoxaprofen as an inhibitor of the lipoxygenase pathway and of the inflammatory monocyte influx significantly suppresses the experimental allergic synovitis. These findings stress upon the important role of the MNP-system in the pathogenesis of rheumatoid arthritis and demonstrate the significance of the monocytes/macrophages as an important target-cell system for antirheumatic drugs.
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PMID:[Pathogenesis and therapy of rheumatoid inflammation]. 348 11

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.
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PMID:Lipoxygenation of arachidonic acid as a source of polymorphonuclear leukocyte chemotactic factors in synovial fluid and tissue in rheumatoid arthritis and spondyloarthritis. 625 25

The leukocyte lipoxygenase products LTB4 and 5-HETE elicit human neutrophil and eosinophil chemotactic responses in vitro and in vivo (Fig. 4), and are present at elevated concentrations in the lesions of some human inflammatory diseases, such as rheumatoid arthritis and the spondyloarthritides. The chemotactic potency of LTB4 is similar to that of the minor fragment of the fifth component of human complement, termed C5a, and is 30- to 300-fold greater than that of 5-HETE and of other natural DHETE isomers. Human neutrophils possess distinct subsets of chemotactic factor receptors that are specific for LTB4 and for 5-HETE, as demonstrated by the selective competitive inhibition of the chemotactic responses to the parent stimuli by acetyl LTB4 and 5-HETE methyl ester, respectively, and by the failure of the lipid chemotactic factors to bind to isolated membrane protein constituents of the human neutrophil receptors for chemotactic formyl-methionyl peptides. LTB4 and 5-HETE also elicit human neutrophil and eosinophil chemokinesis, stimulate the uptake of calcium and D-glucose, and enhance the expression of C3b receptors on the leukocytes; however, they exert only a minimal effect on superoxide generation and lysosomal enzyme release. LTB4, but not 5-HETE, stimulates the release of calcium from previously unexchangeable intraneutrophil pools, as has been described for potent peptide chemotactic factors. Although far less potent than LTC4 and LTD4, LTB4 constricts peripheral airways, enhances mucous secretion in the airways of the lung, and dilates and enhances the permeability of the microvasculature in skin and other organs (Fig. 4). A variety of leukocyte functions, including chemotaxis, D-glucose uptake, and lysosomal enzyme release, are impaired in association with the depletion of endogenous lipoxygenase products. Exogenous 5-HETE reverses some of the functional deficits of HETE-depleted leukocytes. Inhibition of leukocyte lipoxygenase activity also suppresses the intracellular content of hydroperoxyeicosatetraenoic acids and of novel polar metabolites of arachidonic acid that may be critical to the activation of human neutrophils and eosinophils. Thus LTB4 and the less potent 5-HETE are active extracellular mediators of the leukocytic components of hypersensitivity and inflammation and may also serve an important role as intracellular mediators of leukocyte function.
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PMID:Mediation of leukocyte components of inflammatory reactions by lipoxygenase products of arachidonic acid. 628 46

Leukotriene B4 (LTB4), generated from arachidonic acid following lipoxygenase activity by a variety of inflammatory leucocytes, has been shown to be present in synovial fluid from patients with active rheumatoid arthritis. It does not persist as such, being converted to less active metabolites. The role of LTB4 as one of the natural mediators of inflammation is discussed.
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PMID:Leukotriene B4, a mediator of inflammation present in synovial fluid in rheumatoid arthritis. 631 58

Benoxaprofen is a nonsteroidal anti-inflammatory agent that belongs to the arylalkanoic acid class of antirheumatic drugs. Animal studies have demonstrated that it has analgesic, antipyretic, and anti-inflammatory properties. Although benoxaprofen is a relatively weak inhibitor of cyclo-oxygenase in in vitro systems, inhibits lipoxygenase in other systems, and inhibits monocyte migration in some animal models of inflammation, it has not been established that it is unique with regard to these actions. Benoxaprofen undergoes hepatic metabolism via glucuronidation as the primary route of elimination and has a half-life of 28-35 hr. Clinical trials have demonstrated that its analgesic and anti-inflammatory properties are useful in the management of the signs and symptoms of rheumatoid arthritis and osteoarthritis. Once daily dosing of 300-600 mg is effective for many patients. In addition to gastrointestinal intolerance, photosensitivity and onycholysis are the most frequent adverse effects encountered. Recent reports of fatal cholestatic jaundice often associated with nephrotoxicity led to the withdrawal of benoxaprofen from world markets. It is uncertain whether it will once again be available for clinical use.
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PMID:Pharmacology, clinical efficacy, and adverse effects of the nonsteroidal anti-inflammatory agent benoxaprofen. 676 31

The pharmacological profile of a novel dual inhibitor, tepoxalin and of its carboxylic acid metabolite on cyclooxygenase and lipoxygenase pathways was evaluated by in vitro incubation with synovial tissue. Tissue specimens obtained at surgery in rheumatoid arthritis (RA, n = 10) or osteoarthritis (OA, n = 11) patients were incubated. Tepoxalin (10(-7), 10(-6), 10(-5) M) decreased eicosanoid release calculated in % of tyrode control for OA: LTC4 to 71-33%, 6-keto-PGF1a to 37-20%, PGE2 to 29-6%. For RA: LTC4 to 56-22%, 6-keto-PGF1a to 43-22%, PGE2 to 57-32%. Similarly, its metabolite (10(-7), 10(-5)M) decreased release in OA: LTC4 to 99 and 60%, PGE2 to 42 and 20%, 6-keto-PGF1a to 54 and 25%. In RA:LTC4 to 81 and 45%, PGE2 to 61 and 30%, 6-keto-PGF1a to 46 and 18%. Significance (P < 0.05) was achieved for all but 1 group (LTC4 metabolite at 10(-7)M vs tyrode). In summary a marked and dose dependent decrease of LT and PG release was obtained when incubating the dual inhibitor tepoxalin and its active carboxylic acid metabolite with synovial tissue at doses expected to be reached in the joint during therapy.
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PMID:Inhibition of eicosanoid release from synovial organ culture by incubation with tepoxalin and its acid metabolite. 893 87

During the past few decades, intensive collaborative research in the fields of chronic and acute inflammatory disorders has resulted in a better understanding of the pathophysiology and diagnosis of these diseases. Modern therapeutic approaches are still not satisfactory and shock, sepsis and multiple organ failure remain the great challenge in intensive care medicine. However, the treatment of inflammatory diseases like rheumatoid arthritis, ulcerative colitis or psoriasis also represents an unresolved problem. Many factors contribute to the complex course of inflammatory reactions. Microbiological, immunological and toxic agents can initiate the inflammatory response by activating a variety of humoral and cellular mediators. In the early phase of inflammation, excessive amounts of interleukins and lipid-mediators are released and play a crucial role in the pathogenesis of organ dysfunction. Arachidonic acid (AA), the mother substance of the pro-inflammatory eicosanoids, is released from membrane phospholipids in the course of inflammatory activation and is metabolised to prostaglandins and leukotrienes. Various strategies have been evaluated to control the excessive production of lipid mediators on different levels of biochemical pathways, such as inhibition of phospholipase A2, the trigger enzyme for release of AA, blockade of cyclooxygenase and lipoxygenase pathways and the development of receptor antagonists against platelet activating factor and leukotrienes. Some of these agents exert protective effects in different inflammatory disorders such as septic organ failure, rheumatoid arthritis or asthma, whereas others fail to do so. Encouraging results have been obtained by dietary supplementation with long chain omega-3 fatty acids like eicosapentaenoic acid (EPA). In states of inflammation, EPA is released to compete with AA for enzymatic metabolism inducing the production of less inflammatory and chemotactic derivatives.
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PMID:Lipid mediators in inflammatory disorders. 956 39

The fatty acid composition of inflammatory and immune cells is sensitive to change according to the fatty acid composition of the diet. In particular, the proportion of different types of polyunsaturated fatty acids (PUFA) in these cells is readily changed, and this provides a link between dietary PUFA intake, inflammation, and immunity. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds, which have important roles in inflammation and in the regulation of immunity. Fish oil contains the n-3 PUFA eicosapentaenoic acid (EPA). Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators. In addition, EPA is a substrate for cyclooxygenase and lipoxygenase and gives rise to mediators that often have different biological actions or potencies than those formed from AA. Animal studies have shown that dietary fish oil results in altered lymphocyte function and in suppressed production of proinflammatory cytokines by macrophages. Supplementation of the diet of healthy human volunteers with fish oil-derived n-3 PUFA results in decreased monocyte and neutrophil chemotaxis and decreased production of proinflammatory cytokines. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease. Clinical studies have reported that fish oil supplementation has beneficial effects in rheumatoid arthritis, inflammatory bowel disease, and among some asthmatics, supporting the idea that the n-3 PUFA in fish oil are anti-inflammatory and immunomodulatory.
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PMID:Polyunsaturated fatty acids, inflammation, and immunity. 1172 53

We describe a model which can be used for in vitro biocompatibility assays of biomaterials. We studied the in vitro response of human osteoarthritis or rheumatoid arthritis fibroblast-like synoviocytes to Al2O3 or ZrO2 particles by analysing the production of interleukin-1 (IL-1) and interleukin-6 (IL-6) and the metabolism of arachidonic acid via lipoxygenase and cyclo-oxygenase pathways. Our results show that, in these cells and under our experimental conditions, Al2O3 and ZrO2 did not significantly modify the synthesis of IL-1 and IL-6 or the metabolism of arachidonic acid.
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PMID:Effects of alumina and zirconium dioxide particles on arachidonic acid metabolism and proinflammatory interleukin production in osteoarthritis and rheumatoid synovial cells. 1221 91

The immune system is involved in host defense against infectious agents, tumor cells, and environmental insults. Inflammation is an important component of the early immunologic response. Inappropriate or dysfunctional immune responses underlie acute and chronic inflammatory diseases. The n-6 PUFA arachidonic acid (AA) is the precursor of prostaglandins, leukotrienes, and related compounds that have important roles in inflammation and in the regulation of immunity. Feeding fish oil results in partial replacement of AA in cell membranes by EPA. This leads to decreased production of AA-derived mediators, through several mechanisms, including decreased availability of AA, competition for cyclooxygenase (COX) and lipoxygenase (LOX) enzymes, and decreased expression of COX-2 and 5-LOX. This alone is a potentially beneficial anti-inflammatory effect of n-3 FA. However, n-3 FA have a number of other effects that might occur downstream of altered eicosanoid production or might be independent of this effect. For example, dietary fish oil results in suppressed production of proinflammatory cytokines and can modulate adhesion molecule expression. These effects occur at the level of altered gene expression. Fish oil feeding has been shown to ameliorate the symptoms of some animal models of autoimmune disease and to protect against the effects of endotoxin. Clinical studies have reported that oral fish oil supplementation has beneficial effects in rheumatoid arthritis and among some asthmatics, supporting the idea that the n-3 FA in fish oil are anti-inflammatory. There are indications that the inclusion of fish oil in enteral and parenteral formulae is beneficial to patients.
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PMID:N-3 polyunsaturated fatty acids and inflammation: from molecular biology to the clinic. 1284 78


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