Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0409974 (lupus)
 22,386 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using a specific substrate, no leucocyte elastase activity could be detected in 55 synovial fluids, including 29 from patients with rheumatoid arthritis (RA). However, a high percentage of samples contained phagocytic inclusions of elastase, alpha 1-proteinase inhibitor (alpha 1-PI) and alpha 2-macroglobulin (alpha 2-MG) in both the polymorphonuclear (PMN) and mononuclear phagocytes. Immunofluorescence and indirect peroxidase-antiperoxidase staining of articular cartilage (ACA) from 52% of 21 patients with RA and one with juvenile RA (JRA) showed presence of elastase in the superficial layer of microscopically intact but proteoglycan depleted pannus-free ACA. In histologically altered pannus-free RA-ACA superficial elastase deposits were found in 24% of the cases. Adjacent ACA sections contained IgG, C3, alpha 1-PI and rarely alpha 2-MG. RA-ACA below or surrounded by pannus showed close contact with intact and decaying PMN in 62% and 48% of the cases, respectively. ACA specimens from patients with degenerative disease and systemic lupus were negative. These findings strongly suggest that PMN leucocyte elastase is operative in the degradation of RA-ACA and JRA-ACA, and that this activity is largely dependent upon the presence of entrapped immune complexes in such cartilage.
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PMID:Degradation in vivo of articular cartilage in rheumatoid arthritis by leucocyte elastase from polymorphonuclear leucocytes. 705 Dec 54

In the present study, an analysis was made of the expression pattern of thrombospondin-1 (TSP1) and its receptor (CD36) in skin biopsies obtained from healthy volunteers and from patients with lichen planus, lupus erythematosus, cutaneous T-cell lymphoma and psoriasis vulgaris. Using monoclonal antibodies against TSP1 in biopsies from the healthy volunteers and from both clinically involved and uninvolved skin of the patients, a specific peroxidase-positive reaction was detected around the sweat glands in the dermis. In all cases investigated, the CD36-positive lesional keratinocytes remained TSP1-negative. These findings favour the hypothesis that CD36-positive keratinocytes might have some functional relevance via oxidized low-density lipoprotein and/or collagen fibrils, without any connection with TSP1.
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PMID:Expression of thrombospondin-1 (TSP1) and its receptor (CD36) in healthy and diseased human skin. 752 82

In systemic lupus erythematosus accompanied by the abnormal appearance of circulating immune complexes (ICs), Fc gamma receptor (FcR)-mediated IC handling in macrophages including Kupffer cells has been shown previously. However, sinusoidal endothelial cells (SECs) largely ingest soluble immunoglobulin (Ig) G-ICs through FcRs. In this study, the character, antigenic expression, and activity (i.e., ligand-binding capacity of SEC FcRs in NZB/NZW F1 lupus and NZW nonautoimmune mice) were immunohistochemically analyzed using monoclonal antibody (MAb) 2.4G2 to FcRs and peroxidase-antiperoxidase IgG as a ligand on cryosections. MAb 2.4G2 stained SECs and blocked the ligand binding of SEC FcRs in both mice strains. The staining intensities with MAb 2.4G2 in SECs and the FcR activities in SECs alone and all sinusoidal cells in both mice strains reached their maximum values at the age of 5 months. Staining intensities in NZB/W F1 were significantly higher at 1 and 2 months and lower at 9 months than those in NZW. The number of Kupffer cells detected by MAb F4/80 to macrophages in both mice strains gradually increased until 5 months, but their number in NZB/W F1 at 9 months was twice as large as that in NZW. In conclusion, SEC FcRs in mice are low-affinity FcRs that react with MAb 2.4G2. The data of FcR activity suggest no impairment of the FcR-mediated IgG-IC binding on SECs in NZB/W F1 in early life.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Fc receptors in liver sinusoidal endothelial cells in NZB/W F1 lupus mice: a histological analysis using soluble immunoglobulin G-immune complexes and a monoclonal antibody (2.4G2). 754 88

Peripheral blood leukocytes contain a variety of enzymes that are capable of metabolising xenobiotics. The enzyme myeloperoxidase (MPO) appears to be the most important for drug metabolism. MPO is a peroxidase/oxidase and generates the powerful oxidant hypochlorous acid. MPO- or MPO-generated oxidants are capable of oxidizing a wide variety of compounds and a broad range of functional groups, especially those that contain nitrogen and sulfur. Leukocytes have a role in immune response; therefore, reactive intermediates generated by leukocyte metabolism of xenobiotics may have a role in idiosyncratic drug reactions, particularly those that are immune-mediated such as drug-induced lupus or agranulocytosis.
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PMID:Myeloperoxidase-mediated activation of xenobiotics by human leukocytes. 823 77

Impaired clearance of circulating and/or deposited immune complexes (IC) by the mononuclear phagocytic system is one of the major factors in the pathogenesis of IC diseases. MRL/Mp-lpr/lpr (MRL/lpr) lupus mice spontaneously develop a lethal glomerulonephritis associated with IC deposition. The ability of macrophages to degrade phagocytozed IC and regulation of this degradation in MRL/lpr mice were examined. In 4-month-old MRL/lpr mice, macrophages accumulated in the affected glomeruli and these macrophages contained many phagosomes containing electron-dense bodies. When culture supernatant of human T cell line HUT102 was administered intraperitoneally into disease-bearing MRL/lpr mice, degradation of these electron-dense bodies in the macrophages in glomeruli was noted. We developed a quantitative in vitro assay for IC degradation activity of MRL/lpr resident peritoneal macrophages (RPM) using peroxidase-labelled IC derived from MRL/lpr mouse sera. The ability of the RPM to degrade IC was remarkably enhanced by the pretreatment with HUT102 cell products and the related human recombinant cytokines, lymphotoxin and IL-1 alpha. Moreover, pretreatment of RPM from non-diseased MRL/Mp-+/+ mice with the culture supernatant of spleen cells from diseased MRL/lpr mice reduced their IC degradation activity. These results suggested that the ability of macrophages to degrade IC in MRL/Mp strains of mice is under the regulation of cytokines, and the impaired ability in the disease-bearing mice may be the result of abnormalities in the cytokine system in these mice.
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PMID:Immune complex-degradation ability of macrophages in MRL/Mp-lpr/lpr lupus mice and its regulation by cytokines. 828 94

Hydrazines are believed to be oxidized by peroxidases to reactive intermediates responsible for a variety of adverse side effects including cancer and drug-induced lupus. However, hydrazines are regarded as a poor peroxidase substrates because inactivation of the peroxidase occurs during oxidation of these compounds. We have investigated the hypothesis that efficient peroxidase substrates, termed mediators, may stimulate peroxidase-catalyzed oxidation of hydrazines to intermediates capable of causing DNA damage. Oxidation of hydralazine by horseradish peroxidase was stimulated, enzyme inactivation was significantly decreased, and DNA strand breakage was enhanced by the addition of chlorpromazine. Similar results were obtained using other peroxidases, mediators, and hydrazine derivatives. DNA damage required the addition of a minimum of 3 equiv of hydrogen peroxide, suggesting the involvement of a three-electron oxidation product of hydralazine in DNA damage. Efficient substrates may therefore play a critical role in peroxidase-dependent oxidative metabolism and subsequent damage to biological macromolecules by certain chemicals.
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PMID:Peroxidase substrates stimulate the oxidation of hydralazine to metabolites which cause single-strand breaks in DNA. 908 13

Reactive oxygen species (ROS) are cytotoxic, causing inflammatory disease, including tissue necrosis, organ failure, atherosclerosis, infertility, birth defects, premature aging, mutations and malignancy. ROS are produced in the metabolism of drugs and industrial chemicals by (i) one-electron peroxidase oxidations to form cation radicals, (ii) cytochrome P450 metabolism to free radical products, (iii) stabilisation of the ROS-generator, CYP2E1, and (iv) futile cycling of other cytochromes P450. ROS production initiates inflammation which unless quenched may result in chronic inflammatory disease states, e.g. hepatitis, nephritis, myositis, scleroderma, lupus erythematosus, multiple system organ failure. Quenching of ROS is affected by the redox buffer, glutathione (GSH), and the antioxidants, ascorbic acid, tocopherols, retinoids, in conjunction with the redox enzymes, GSH reductase, GSH peroxidase, catalase and superoxide dismutase. Many industrial workers with symptoms of systemic inflammation, resulting from exposure to toxic chemicals, are diagnosed as having rheumatoid arthritis, virus infections, or other microbial lesions, largely because many physicians are unaware that exposure to certain chemicals can initiate inflammatory disease states.
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PMID:Chemical toxicity and reactive oxygen species. 911 92

Naturally occurring polyreactive anti-DNA mAbs derived from a nonimmunized (NZB x NZW)F1 mouse with spontaneous lupus erythematosus penetrated and accumulated in the nuclei of a variety of cultured cells. These mAbs and their F(ab')2 and Fab' fragments, covalently coupled to fluorescein, peroxidase, or a 15-mer polynucleotide, also translocated to the cell nuclei. A 30-amino acid peptide corresponding to the combined sequences of the complementary-determining regions 2 and 3 of the heavy chain variable region of one mAb was able to penetrate into the cytoplasm and nucleus of cells of several lines. This peptide recognized DNA and was strongly polyreactive. Streptavidin-peroxidase conjugates complexed with the N-biotinylated peptide were rapidly translocated into cells. Similarly, peroxidase or anti-peroxidase polyclonal antibodies covalently coupled to the N-cysteinylated peptide through an heterobifunctional maleimide cross-linker were also rapidly internalized and frequently accumulated in nuclei. The peptide carrying 19 lysine residues at its N-terminal was highly effective in transfecting 3T3 cells with a plasmid containing the luciferase gene. Thus, penetrating mAbs and derived peptides are versatile vectors for the intracellular delivery of proteins and genes.
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PMID:Polyreactive anti-DNA monoclonal antibodies and a derived peptide as vectors for the intracytoplasmic and intranuclear translocation of macromolecules. 957 29

Long-term treatment of hypertensive disorders with hydralazine has resulted in some patients developing hepatitis and lupus erythematosus, an autoimmune syndrome. The concentration of hydralazine required to cause 50% cytotoxicity in 2 h (LC(50)) toward isolated rat hepatocytes was found to be 8 mM. Cytotoxicity was delayed by the P450 inhibitor, 1-aminobenzotriazole, suggesting that P450 catalyzed the formation of toxic metabolites from hydralazine. No hydralazine-induced oxidative stress was apparent as there was little effect on hepatocyte lipid peroxidation, protein carbonyl formation, intracellular H(2)O(2), or hepatocyte GSH levels and no effect of butylated hydroxyanisole (BHA) on cytotoxicity. Drug-induced hepatotoxicity in vivo has often been attributed to infiltrating inflammatory cells, for example, neutrophils or resident Kupffer cells whose NADPH oxidase generates H(2)O(2), when activated. The effect of a nontoxic continuous infusion of H(2)O(2) on hydralazine cytotoxicity was investigated. It was found that H(2)O(2) increased hepatocyte susceptibility to hydralazine 4-fold (LC(50), 2 mM). Cytotoxicity was still prevented by the P450 inhibitor but now involved some oxidative stress as shown by increased protein carbonyls, endogenous H(2)O(2), and GSH oxidation. Lipid peroxidation was not increased, and cytotoxicity was not inhibited by BHA. Cytotoxicity, however, was inhibited by 4-hydroxy-2,2,6,6-tetramethylpiperidene-1-oxyl (TEMPOL), a ROS scavenger. Because neutrophils or Kupffer cells release myeloperoxidase on activation, the effect of adding peroxidase to the hepatocytes exposed to H(2)O(2) on hydralazine cytotoxicity was investigated. It was found that peroxidase/H(2)O(2) increased hepatocyte susceptibility to hydralazine 80-fold (LC 50, 0.1 mM). Furthermore, cytotoxicity occurred following extensive oxidative stress that included lipid peroxidation, and cytotoxicity that was now prevented by the antioxidant BHA. These results indicate that three cytotoxic pathways exist for hydralazine: a P450-catalyzed pathway not involving oxidative stress, a P450/H(2)O(2)-catalyzed oxidative stress-mediated cytotoxic pathway not involving lipid peroxidation, and a peroxidase/H(2)O(2)-catalyzed lipid peroxidation-mediated cytotoxic pathway.
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PMID:Accelerated cytotoxic mechanism screening of hydralazine using an in vitro hepatocyte inflammatory cell peroxidase model. 1839 51

The accelerated atherosclerosis that occurs in some patients with systemic lupus erythematosus (SLE) has a complex pathogenesis, including alterations in lipids, inflammation and the immune system. In this article, we review the evidence that peroxidase-related alteration of normal, protective high-density lipoprotein (HDL) converts them to pro-inflammatory HDL (piHDL), characterized by lower content of the cholesterol transport lipoprotein ApoA1 and impaired function of the antioxidant enzyme paroxonase, which prevents oxidation of low-density lipoprotein (LDL). Forty-five per cent of women with SLE have piHDL compared with 20% of patients with rheumatoid arthritis and 4% of healthy controls. The presence of piHDL increases risk for coronary artery events and carotid artery plaque. Another result of lipid oxidation in patients with SLE is generation of highly oxidized LDL and phospholipids (PL), probably stimulating antibodies to OxPL phospholipids. These antibodies along with promoting thrombosis also interfere with deposits of Annexin V onto endothelial cells, which probably promote increased instability of atherosclerotic plaque. Thus, piHDL and anti-OxPL promote plaque formation, plaque instability and thrombosis, accounting for some of the large increase in atherosclerosis and coronary artery events in SLE.
Lupus 2008 May
PMID:Atherosclerosis and systemic lupus erythematosus: the role of altered lipids and of autoantibodies. 1849 Apr 9


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