Nitric oxide synthesis is increased in patients with systemic lupus erythematosus.
ABSTRACT Nitric oxide (NO) is believed to have a role in the inflammatory process. NO production was measured in 26 patients with systemic lupus erythematosus (SLE) and 20 healthy volunteers, using spectrophotometrically determined serum nitrite and citrulline as surrogate markers. Both nitrite and citrulline levels were significantly higher in patients with SLE than in controls (P < 0.001). Twelve and 10 patients, respectively, with SLE had nitrite and citrulline levels that were two standard deviations higher than the mean level of controls. These patients had a significantly higher measure of disease activity (SLE Disease Activity Index). These data show that there is increased NO production in SLE and that it may serve as a marker for disease activity.
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ABSTRACT: MRL-lpr/lpr mice spontaneously develop various manifestations of autoimmunity including an inflammatory arthropathy and immune complex glomerulonephritis. This study examines the role of nitric oxide, a molecule with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr autoimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrate (an in vivo marker of nitric oxide production) than did mice of normal strains and MRL-(+/+) and B6-lpr/lpr congenic strains. In addition, MRL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activity, and certain tissues from MRL-lpr/lpr mice had increased expression of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of NG-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of inflammatory arthritis in MRL-lpr/lpr mice. By using interspecific backcross mice, the gene for inducible NOS (Nosi) was mapped to mouse chromosome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced susceptibility to renal disease in an MRL-lpr/lpr cross. However, the chromosomal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mice. These results suggest that elevated nitric oxide production could be important in the pathogenesis of autoimmunity, and that treatments to block the production of nitric oxide or block its effects might be valuable therapeutically.Journal of Experimental Medicine 03/1994; 179(2):651-60. · 13.21 Impact Factor
- Annual Review of Biochemistry 02/1994; 63:175-95. · 27.68 Impact Factor
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ABSTRACT: Vascular endothelial cells contain a constitutive nitric oxide (NO) synthase that is Ca2(+)-dependent. In addition, we have found that these cells express, after activation with interferon-gamma and lipopolysaccharide, an inducible Ca2(+)-independent NO synthase that is distinct from the constitutive enzyme. The generation of NO by this enzyme was detectable after a lag period of 2 hr, reached a maximum between 6 and 12 hr, and was maintained for the duration of the experiment (48 hr). The expression of the inducible NO synthase was inhibited by the protein synthesis inhibitor cycloheximide, a compound that had no direct effect on the activity of either of the two enzymes. Furthermore, hydrocortisone and dexamethasone, but not progesterone, inhibited the expression of the inducible enzyme, without directly affecting the activity of either enzyme, without directly affecting the activity of either enzyme. The effect of these steroids was inhibited in a concentration-dependent manner by cortexolone, a partial agonist of glucocorticoid receptors. Thus, the inhibition of the induction of an NO synthase by glucocorticoids is a receptor-mediated event involving the inhibition of the synthesis of mRNA for de novo synthesis of this enzyme. The induction of this NO synthase may contribute to the pathophysiology of immunologically based conditions. Furthermore, the inhibition of this induction by anti-inflammatory steroids may explain some of the therapeutic and adverse effects of these compounds.Proceedings of the National Academy of Sciences 01/1991; 87(24):10043-7. · 9.74 Impact Factor