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)

A chemiluminescent assay was used to measure generation of excited oxygen species by peripheral blood monocytes obtained from normal controls (NC) and patients with rheumatoid arthritis (RA). Whole peripheral blood mononuclear cells (PBMC) and adherent cells (AdhC) from RA patients showed a significantly higher chemiluminescent response to opsonized zymosan at certain observation times than cells from NC. There was no significant difference however in response to stimulation by calcium ionophore (CI). Gold sodium thiomalate (GSTM) significantly inhibited the peak response of fresh PBMC and AdhC (from both RA and NC) to zymosan and CI. GSTM inhibited only the peak response of fresh cells to zymosan; by contrast cells cultured with GSTM for 72 h showed inhibition at all time periods. The effect of GSTM was dependent on dosage and duration of incubation with cells. The addition of GSTM after zymosan stimulation did not inhibit chemiluminescence. GSTM appears to act upon cellular events following membrane activation which culminates in the generation of excited oxidative species. These results suggest a mechanism of action for GSTM in RA by inhibition of monocyte and macrophage dependent generation of oxy radicals and related excited oxygen species.
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PMID:Monocyte dependent excited oxygen radical generation in rheumatoid arthritis: inhibition by gold sodium thiomalate. 631 36

According to the original hypothesis, synovial tissue (ST) oedema and synovial fluid (SF) volume increase contribute to local hypoxia and metabolic alterations and to inflammation (A 1). Studies on biochemical mechanisms (A 2) in synovitides show that the SF volume correlates to SF hypoxia that correlates to lactate increase, acidosis and to some decrease in glucose. Normal ST produces lactate by glycolytic and pentose phosphate pathway activity, both, as well as the normally low oxygen utilization, being increased in synovitides . In ST very little carbohydrate seems to pass directly into the citric acid cycle and oxidation of fat may be involved, but it is not known if the fat is carried to ST by the blood or if it is synthetized locally (B). ST oedema and effusions may be most important as causes of local hypoxia (C). Acidosis alters physico-chemical properties of proteins, possibly changing their chemotactic and antigenic qualities, etc. Hypoxia and fuel supply might be related to fibroblast, macrophage and neutrophil reactions, and, in view of the high metabolic demands of villi, they may contribute to, e.g., ST necroses, and to erosions (D). I shall summarize some essentials of my present views on the pathogenesis (E 1 a) and causes in single cases (E 3 b) of synovitis, and comment on two other new hypotheses on rheumatoid arthritis (E 2) and on therapeutic (E 4) and other implications of this concept (E).
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PMID:A hypothesis on the pathogenesis of rheumatoid and other non-specific synovitides. IV A. The possible intermediate role of local hypoxia and metabolic alterations. 637 58

The generation of chemiluminescence (CL)-detectable oxygen radicals by normal human polymorphonuclear leukocytes (PMN) after challenging with systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) sera is described. CL was measured in a luminol-dependent assay and referred to a standard obtained when performed immune complexes (Ic) (human tetanus toxoid-antitoxoid Ic resuspended in normal pooled serum) were tested on PMN. Normal sera gave rise to CL activity by PMN between 0% and 50% of the standard Ic (mean +/- standard error of the mean (SEM): 20.7 +/- 4.8). Sera from SLE and RA patients induced strikingly different biological effects on PMN. SLE sera generally induced a high CL-detectable generation of oxygen metabolites which may be causally related to the intense tissue damage (vasculitis) frequently observed in this disease. In contrast to SLE, RA sera induced a CL-detectable respiratory burst by PMN that was included in the normal range. Thus, the biological effects of these sera in terms of stimulation of toxic oxygen radical generation by phagocytes are quite different. This generation of oxygen radicals might reflect a different clearance of circulating Ic by PMN in SLE and RA disease.
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PMID:Differential generation of chemiluminescence--detectable oxygen radicals by normal polymorphonuclear leukocytes challenged with sera from systemic lupus erythematosus and rheumatoid arthritis patients. 649 92

Neutrophils from the synovial fluid (SFN) of 10 patients with active rheumatoid arthritis (RA) were investigated to determine the generation of oxygen intermediates (OI) (O2-, H2O2, OH .), chemiluminescence, and lysosomal enzymes (lysozyme and beta-glucuronidase). Lymphocytes from healthy individuals were cocultured at 37 degrees C for 17 hr with SFN from the patients and the number of OKT4+, OKT8+, and OKT3+ cells and the response to mitogens were determined. A markedly increased OI and slightly elevated lysosomal enzyme levels were observed in SFN from patients. Coculture of lymphocytes with SFN resulted in a decreased number of OKT4+ and OKT8+ cells and a greatly reduced response to Con A and mildly diminished response to PHA, while OKT3+ cells were not affected. The simultaneous addition of superoxide dismutase and catalase restored the impairment of monoclonal antibody reaction and lymphocyte responsiveness almost to control levels. It is suggested that the disturbed immunoreactivity of synovial fluid lymphocytes from RA patients may be due to increased OI generated by stimulated neutrophils.
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PMID:Effect of stimulated neutrophils from the synovial fluid of patients with rheumatoid arthritis on lymphocytes--a possible role of increased oxygen radicals generated by the neutrophils. 660 65

Levels of free sulph-hydryl (SH) groups are depressed in the sera of patients with rheumatoid arthritis, especially during active disease. However, the mechanism underlying this effect is not known. We have investigated several oxidative species generated during the inflammatory process for their ability to react with serum SH in vitro. Our results show that serum oxidase enzymes (e.g. caeruloplasmin) do not have this activity but that "active oxygen species" generated either by an enzymatic reaction (xanthine plus xanthine oxidase) or by neutrophils stimulated with heat-aggregated IgG cause rapid oxidation of serum SH groups. The use of selective inhibitors of active oxygen species has demonstrated that this reaction is mediated by hydrogen peroxide. This compound is secreted in considerable amounts by activated phagocytic cells, especially neutrophils. Thus, serum SH levels may reflect phagocytic activity in patients with rheumatoid arthritis. We suggest that serum SH groups act as important extracellular scavengers of peroxides and so help to protect cells from damage by these molecules.
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PMID:The oxidation of serum sulph-hydryl groups by hydrogen peroxide secreted by stimulated phagocytic cells in rheumatoid arthritis. 671 52

The effects of D-penicillamine (D-Pen) in rheumatoid arthritis suggest that the drug may be anti-inflammatory and immunosuppressive. Paradoxically D-Pen therapy may also induce antibody formation, and autoimmune disease. D-Pen is not consistently effective in animal models of immune disease. It is weakly suppressive in cellular responses to mitogens, but has a more pronounced effect on macrophage-dependent mixed leukocyte responses. The drug has an inconsistent effect on various components of the inflammatory reaction but under certain circumstances inhibits oxygen radical generation by monocyte/macrophages.
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PMID:Effects of D-penicillamine on inflammatory and immune reactions. 672 24

Oxygen free radicals are probably involved in the pathogenesis of rheumatoid arthritis (RA). The enzymes involved in protection against oxygen free radicals and H2O2 (superoxide dismutase, catalase, and glutathione peroxidase) were measured. Superoxide dismutase was not increased, glutathione peroxidase was slightly and catalase was strongly elevated in RA synovial fluid (SF) compared with control SF. Although these enzymes are present in SF, the activities are insufficient to protect against oxygen free radicals and H2O2. In contrast to transferrin, ferritin was increased in RA synovial fluid. Ceruloplasmin was also elevated. When rat liver microsomes were used as a target for oxygen free radicals, serum and SF were both protective. Gel filtration experiments showed that the fraction pattern in which there was maximal protective potential against lipid peroxidation corresponded closely to the level of ceruloplasmin. After removal of ceruloplasmin from serum or SF, about 70% of the protective capacity disappeared. It is concluded that ceruloplasmin is an important protector against oxygen free radicals.
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PMID:Protective factors against oxygen free radicals and hydrogen peroxide in rheumatoid arthritis synovial fluid. 674 61

To investigate the impact of synovial fluid volume on oxygen tension (PO2) and other metabolic correlates, 24 specimens of synovial fluid from the knees of 22 patients were analyzed for volume, number of leukocytes (WBC), pH, PO2, PCO2, glucose, protein, and complement (CH50) levels. Concurrent arterial blood samples were obtained in 21 instances. Synovial fluid PO2 values varied inversely with volumes of synovial fluid (r = -0.54, P less than 0.01), but when patients with rheumatoid arthritis were excluded, the correlation was more significant (r = -0.76, P less than 0.001). When synovial fluid PO2 dropped below 45 mm Hg, intraarticular acidosis resulted. The decrease in pH (r = 0.93, P less than 0.001), the lowering of glucose values (r = 0.89, P less than 0.001), and the rise in PCO2 (r = -0.79, P less than 0.01) can be explained by a shift toward anaerobic metabolism coupled with the impaired elimination of its products. Systemic acidosis and hypoxia were not found. Intraarticular hypoxia most likely represents circulatory imbalance at the level of the synovial membrane, although an inverse relationship of synovial fluid PO2 and WBC was also noted. Complement and protein levels had no correlation with volume, pH, or respiratory gas tensions of synovial fluids. Our data support the importance of the effective blood flow to the joint in maintaining homeostasis. The volume of synovial effusion and the compliance of the joint capsule appear to be important determinants of the articular blood supply.
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PMID:Reciprocal relationship of synovial fluid volume and oxygen tension. 678 98

It has been shown that gold accumulates in macrophages. In vitro studies have also shown that long-term anti-inflammatory and immuno-regulatory effects on these cells may be responsible for the effectiveness of gold in the treatment of rheumatoid arthritis. However, the relevance of this information to the in vivo circumstance is largely untested. In this study, the effect of gold sodium thiomalate (AuTM) on rat alveolar macrophage (AM) lysosomal enzymes, bacterial killing, and metabolic activities associated with phagocytosis were assessed after in vivo administration. The activities of beta-glucuronidase, acid phosphatase, and lysozyme were inhibited 1 day following a single AuTM injection (50 mg/kg, subcutaneous). However, lysozyme returned to normal, while the activities of beta-glucuronidase and acid phosphatase were elevated from 4 to 12 days thereafter. When AuTM was administered weekly for 8 weeks, the activities of acid phosphatase and beta-glucuronidase were elevated throughout, while lysozyme was largely unaffected. The increased lysosomal enzyme activities were not due to contamination of polymorphonuclear leukocytes. These long-term effects of AuTm on enzyme activity were in marked contrast to its in vitro effect which inhibited the activities of beta-glucuronidase and acid phosphatase. No effect of AuTM administration on the release of beta-glucuronidase upon phagocytosis of opsonized zymosan was observed. At 1 day following a single AuTM injection or 3 days after a second weekly injection, in vivo bactericidal activity of AM toward S. aureus was diminished. This bacterial killing defect was not due to decrease phagocytosis; the in vivo binding and ingestion of bacteria were normal. The defect correlated with imparied metabolic activities associated with phagocytosis, namely a significant decrease in the reduction of nitroblue tetrazolium and the stimulation of the hexose monophosphate shunt. This may be an attractive anti-inflammatory effect in light of the destructive potential of the reactive oxygen species produced by macrophages in an arthritic circumstance.
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PMID:Effect of in vivo administration of gold sodium thiomalate on rat macrophage function. 681 20

Activation of the neutrophil surface membrane may occur with a variety of stimuli, leading to enhanced glucose oxidation via the hexose monophosphate shunt and production of toxic oxygen radicals such as superoxide anion. This metabolic stimulation may be accompanied by light emission or chemiluminescence. The objective of these studies was to determine the effects of soluble and insoluble immune complexes, IgG aggregates, and rabbit anti-neutrophil serum on neutrophil activation as measured by chemiluminescence. Also, the uptake of immune complexes by neutrophils was determined and was correlated with the solubility of the complexes and the levels of induced chemiluminescence. The results indicate that stimulation of neutrophil chemiluminescence and uptake of immune complexes by neutrophils were both closely correlated with the percent precipitation of the immune complexes. Insoluble immune complexes that were avidly ingested by neutrophils also stimulated maximum levels of chemiluminescence. Nevertheless, elevated levels of chemiluminescence were induced by soluble immune complexes that were poorly ingested by neutrophils. Similarly, soluble aggregated IgG induced elevated levels of neutrophil chemiluminescence in a dose-dependent manner. Aggregated IgG induced up to sixfold higher levels of neutrophil chemiluminescence than did equal amounts of monomeric IgG. Finally, rabbit anti-neutrophil serum also caused increased levels of neutrophil chemiluminescence. Since previous studies have shown that sera from some patients with rheumatoid arthritis and Felty's syndrome have increased amounts of neutrophil-binding IgG due to the presence of both immune complexes and neutrophil-reactive antibodies, the effect of these sera on neutrophil chemiluminescence was studied. Positive correlations were observed between the level of neutrophil chemiluminescence induced by the sera and the amount of serum IgG neutrophil-binding activity (r = 0.72, p less than 0.001) as well as the level of immune complexes determined by C1q binding (r = 0.76, p less than or equal to 0.001). Such neutrophil activation by immune complexes or antibodies may reflect production of toxic oxygen radicals and could subsequently affect neutrophil function.
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PMID:Stimulation of human neutrophil chemiluminescence by soluble immune complexes and antibodies to neutrophils. 697 84


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