Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024141 (systemic lupus erythematosus)
 44,322 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Factors that potentially affect the generation of excess low molecular weight DNA (LMW-DNA) in cultured phytohemagglutinin (PHA)-stimulated lymphocytes of patients with systemic lupus erythematosus (SLE) were studied because this species of DNA is consistently found and this DNA may play a role in the pathogenesis of the disease. Superoxide dismutase (SOD; 0.05 mg/mL), a scavenger of free radical oxygen, decrease LMW-DNA formation in lymphocytes by 22%. Co-cultivation with cysteamine, a second scavenger of free radical oxygen and a sulfhydryl radioprotective agent, resulted in a 32% decrease in the generation of excess LMW-DNA at a concentration of 0.5 x 10(-3) mol/L and largely prevented its formation at 1.0 x 10(-3) mol/L. Other free radical scavengers (catalase, mannitol, vitamins C and E), cyclooxygenase inhibitors (ibuprofen and aspirin), a xanthine oxidase inhibitor (allopurinol), and an iron chelator (desferoxamine) did not affect excess LMW-DNA formation. Glutathione (1 x 10(-3) mol/L) had no effect and cysteine was toxic. Because scavengers of free radicals might be useful in the therapy of lupus, a trial of cysteamine (30 to 60 mg/kg/d) was administered to six acutely ill patients with SLE. A therapeutic benefit was not demonstrated, and some patients had exacerbation of disease. Lymphocyte cell growth from control and lupus subjects was stimulated when cysteamine, 1 x 10(-5) to 1 x 10(-4) mol/L was added to the media, but inhibited at concentrations of 2 x 10(-4) mol/L or greater. These studies suggest that the autooxidation and toxicity of high-dose cysteamine preclude its therapeutic use as a free radical scavenger.
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PMID:Scavengers of free radical oxygen affect the generation of low molecular weight DNA in stimulated lymphocytes from patients with systemic lupus erythematosus. 224 68

After structure-activity relationship studies (SAR) on a novel class of substituted thiazolo(3,2-b)(1,2,4)triazin-7-ones, HWA-131 (3-(3,5-di-tert.butyl-4-hydroxyphenyl)-7H-thiazolo(3,2-b)(1,2,4)triaz in-7-one) was selected for incremental pharmacological investigations. This compound was effective in not only preventing, but also curing established arthritic disorders of rats such as adjuvant and type II collagen arthritis as well as those of mice such as chronic graft-versus-host (CGVH) disease, a model for systemic lupus erythematosus (SLE). Further, this non-immunosuppressive drug effectively inhibited the carrageenan-induced paw oedema, attenuated the active Arthus reaction, and demonstrated antierythema as well as antipyretic activity. Part of the antiinflammatory effects of this new compound is most probably related to its antioxidative activity, as well as inhibition of lipoxygenase metabolites. HWA-131's good gastric tolerance may have to do with its limited ability to inhibit the production of cyclooxygenase metabolites. Based on our data, we are sure that HWA-131 will be an effective nonsteroidal antiinflammatory agent, with immunomodulating properties, to combat human autoimmune disorders.
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PMID:Substituted 3-phenyl-7H-thiazolo(3,2-b)(1,2,4)triazin-7-ones as antiinflammatory agents with immunomodulating properties. 253 81

We have examined the urinary excretion of stable immunoreactive eicosanoids in 23 female patients with systemic lupus erythematosus (SLE), 16 patients with chronic glomerular disease (CGD), and 20 healthy women. SLE patients had significantly higher urinary thromboxane B2 (TXB2) and prostaglandin (PG) E2 excretion and significantly lower 6-keto-PGF1 alpha than did healthy women. In contrast, CGD patients only differed from controls for having reduced 6-keto-PGF1 alpha excretion. The group of SLE patients with active renal lesions differed significantly from the group with inactive lesions for having a lower creatinine clearance and urinary 6-keto-PGF1 alpha and higher urinary TXB2. Higher urinary TXB2 excretion was associated with comparable platelet TXB2 production in whole blood, undetectable TXB2 in peripheral venous blood, and unchanged urinary excretion of 2,3-dinor-TXB2. A significant inverse correlation was found between urinary TXB2 and creatinine clearance rate (CCr). In contrast, the urinary excretion of 6-keto-PGF1 alpha showed a significant linear correlation with both CCr and para-aminohippurate clearance rate (CPAH). In four SLE and seven CGD patients, inhibition of renal cyclooxygenase activity by ibuprofen was associated with a significant reduction in urinary 6-keto-PGF1 alpha and TXB2 and in both CCr and CPAH. However, the average decrease in both clearances was 50% lower in SLE patients than in CGD patients, when fractionated by the reduction in urinary 6-keto-PGF1 alpha or PGE2 excretion. We conclude that the intrarenal synthesis of PGI2 and TXA2 is specifically altered in SLE. Such biochemical alterations are associated with changes in glomerular hemodynamics and may play a role in the progression of SLE nephropathy.
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PMID:Functional significance of renal prostacyclin and thromboxane A2 production in patients with systemic lupus erythematosus. 390 Jan 32

Dietary supplementation of fish oil as the exclusive source of lipid suppresses autoimmune lupus in MRL-lpr mice. This marine oil diet decreases the lymphoid hyperplasia regulated by the lpr gene, prevents an increase in macrophage surface Ia expression, reduces the formation of circulating retroviral gp70 immune complexes, delays the onset of renal disease, and prolongs survival. We show that a fatty acid component uniquely present in fish oil but not in vegetable oil decreases the quantity of dienoic prostaglandin E, thromboxane B, and prostacyclin normally synthesized by multiple tissues, including kidney, lung, and macrophages, and promotes the synthesis of small amounts of trienoic prostaglandin in autoimmune mice. We suggest that this change in endogenous cyclooxygenase metabolite synthesis directly suppresses immunologic and/or inflammatory mediators of murine lupus.
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PMID:A fish oil diet rich in eicosapentaenoic acid reduces cyclooxygenase metabolites, and suppresses lupus in MRL-lpr mice. 391 11

Dietary marine lipids markedly reduce the severity of glomerulonephritis and its associated mortality in inbred strains of mice developing autoimmune disease, a model for human systemic lupus erythematosus. We report here the influence of varying the dose of menhaden oil and the timing of its administration on the mortality of female (NZB x NZW) F1 mice. After ingesting 25 wt% menhaden oil (MO) for periods of 1.5 weeks to 12 months, there was a stable content of tissue n-3 fatty acids, with total n-3 fatty acids of 28% and 35% in spleen and liver, respectively. The extent of protection from mortality was dependent on the dose of MO with marked protection at doses of 11 to 25%, marginal protection at 5.5% and no protection at 2.5% MO. Delay in the institution of MO until ages 5 or 7 months still resulted in large reductions of mortality. Conversely, institution of a MO diet from 6 weeks until ages 5 to 7 months followed by a change to beef tallow resulted in little protection. Serum levels of 4 cyclooxygenase products were reduced ranging from 26 to 76% in mice fed MO diets, compared to mice fed beef tallow, based on radioimmunoassay. The degree of reduction of mortality on different doses of MO was correlated best with tissue levels of C22:5, and levels of C20:5 and C22:6 were similar at high and low doses of MO, suggesting that levels of 22:5 may be related to the protective effects of marine lipids on autoimmune disease.
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PMID:The protective effect of dietary fish oil on murine lupus. 404 78

We examined the effects of two prostaglandin synthetase inhibitors, aspirin and oxaprozin, on the development of lupus-like disease in MRL/1 mice. Daily oral administration of 100 mg/kg of these compounds over a period of 3 months significantly reduced thymic lymphoid hyperplasia. In addition, aspirin but not oxaprozin significantly lowered total lymphocyte counts in the peripheral blood. Other drug-related changes, including reduced hyperplasia in the spleen and lymph nodes and an improvement in kidney vasculitis by aspirin, did not reach statistical significance. Neither aspirin nor oxaprozin influenced the circulating levels of anti-ds DNA antibodies or the severity of kidney glomerulonephritis. While the overall effects of these cyclooxygenase inhibitors were not dramatic, the results do indicate that further studies are warranted to determine the precise therapeutic role, if any, for PG-synthetase inhibitors in lupus-like disease.
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PMID:Effects of oral aspirin and oxaprozin on the development of lupus-like disease in MRL/1 mice. 643 13

In lupus nephritis (LN), renal thromboxane A2 (TXA2) production is increased, and inhibition of TXA2 activity improves renal function. In patients with LN, renal function depends very much on vasodilatory prostaglandins, and indeed inhibiting the prostaglandin-forming enzyme cyclooxygenase (COX) with aspirin or related compounds was detrimental on renal hemodynamics in these patients. There are no data so far on whether the excessive TXA2 production in LN derives from upregulation of type I or type II isoforms of COX. It was found that TXB2 synthesis and COX-2 gene expression were higher in peripheral blood mononuclear cells from patients with active LN compared to patients in the inactive form of the disease and to healthy subjects. Unlike COX-2, levels of COX-1 mRNA were comparable in lupus patients and control subjects and were not influenced by the disease activity. Immunoperoxidase studies on kidney biopsies showed COX-1 staining in glomerular arterioles and other renal vessels, with no evident difference between lupus biopsies and control specimens taken from either individuals who were free of renal disease or patients with non-lupus nephropathies. In contrast, COX-2 staining was definitely stronger in specimens from patients with active LN than control specimens. In active LN, COX-2-specific staining was localized mainly in the glomeruli, with a weaker signal on tubuli and in the interstitium. Double-staining studies with an antibody against the macrophage marker CD68 and an anti-COX-2 antibody definitely showed that COX-2 and CD68 often colocalized on the same cell, with only occasional glomerular COX-2-stained mesangial areas. Patients with non-lupus nephropathies had no increase in renal COX-2 expression. These results indicate that COX-2 upregulation is a specific finding of active LN and that monocytes infiltrating the glomeruli contribute to the exaggerated local synthesis of TXA2. If this is correct, COX-2 may soon become a target for therapeutic intervention in this disease.
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PMID:Upregulation of renal and systemic cyclooxygenase-2 in patients with active lupus nephritis. 964 30

MRL/Mp-lpr/lpr (MRL/lpr) mice develop immune complex glomerulonephritis similar to human lupus. Glomerular mesangial cells are key modulators of the inflammatory response in lupus nephritis. When activated, these cells secrete inflammatory mediators including NO and products of cyclooxygenase perpetuating the local inflammatory response. PGJ2, a product of cyclooxygenase, is a potent in vitro inhibitor of macrophage inflammatory functions and is postulated to function as an in vivo inhibitor of macrophage-mediated inflammatory responses. We hypothesized that in lupus, a defect in PGJ2 production allows the inflammatory response to continue unchecked. To test this hypothesis, mesangial cells were isolated from MRL/lpr and BALB/c mice and stimulated with IL-1beta or LPS plus IFN-gamma. In contrast to the 2- to 3-fold increase in PGJ2 production by stimulated BALB/c mesangial cells, supernatant PGJ2 did not increase in MRL/lpr mesangial cell cultures. NO production in stimulated MRL/lpr and BALB/c mesangial cells, was blocked by PGJ2 and pioglitazone. These studies suggest that abnormalities in PGJ2 production are present in MRL/lpr mice and may be linked to the heightened activation state of mesangial cells in these mice.
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PMID:Inhibition of mesangial cell nitric oxide in MRL/lpr mice by prostaglandin J2 and proliferator activation receptor-gamma agonists. 1064 Jul 67

Nearly 80% of patients with systemic lupus erythematosus (SLE) are treated with NSAIDs for fever, arthritis, serositis and headaches. This article reviews currently available literature on non-selective and selective inhibitors of cyclooxygenases, with an emphasis on the efficacy and safety profile reported in SLE patients. All NSAIDs, regardless of their cyclooxygenase selectivity, induced renal side effects including sodium retention and reduction in glomerular filtration rate. In addition, lupus nephritis is a risk factor for NSAID-induced acute renal failure. NSAID-induced hepatotoxicity is increased in SLE patients in addition to cutaneous and allergic reactions. Finally, aseptic meningitis has been reported more frequently in NSAID-treated SLE patients. Nevertheless, NSAIDs can safely be prescribed to most lupus patients provided that their administration is re-evaluated on a regular basis and the patient is closely monitored.
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PMID:Risk:benefit ratio of nonsteroidal anti-inflammatory drugs in systemic lupus erythematosus. 1526 45

Special populations of T helper cells drive B cells to produce IgG class switched, pathogenic autoantibodies in lupus. The major source of antigenic determinants (epitopes) that trigger interactions between lupus T and B cells is nucleosomes of apoptotic cells. These epitopes can be used for antigen-specific therapy of lupus. Secondly, the autoimmune T cells of lupus are sustained because they resist anergy and activation-induced programmed cell death by markedly upregulating cyclooxygenase (COX) 2 along with the antiapoptotic molecule c-FLIP. Only certain COX-2 inhibitors block pathogenic anti-DNA autoantibody production in lupus by causing death of autoimmune T helper cells. Hence COX-2 inhibitors may work independently of their ability to block the enzymatic function of COX-2, and structural peculiarities of these select inhibitors may lead to better drug discovery and design.
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PMID:T-helper cell intrinsic defects in lupus that break peripheral tolerance to nuclear autoantigens. 1563 May 91


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