ABSTRACT
Nitric oxide may exhibit proinflammatory features. NO synthase (NOS) type 2 (NOS2) is overexpressed, and NO is overproduced in rodent models of inflam mation. Blockage of NO production by administration of NOS inhibitors prevents or reduces various types of induced inflammation in rodents. Humans with the autoimmune disease rheumatoid arthritis have increased levels of NOS2 and NO production in their diseased synovia and in blood leukocytes, and the levels of NOS2 correlate significantly with disease activity. We have shown that auto immune MRL-lpr/lpr mice overexpress NOS2 and overproduce NO in an agedependent fashion that parallels expression of arthritis, glomerulonephritis, and vasculitis. The mice have high levels of nitrosylhemoglobin in their blood and high levels of a nitrosyl nonheme, iron protein in their diseased kidneys. Block ing NO production by oral administration of the NOS inhibitor NG-monomethyl-L-arginine reduced the arthritis, glomerulonephritis, and vasculitis, while it did not modify serum anti-DNA antibody levels or glomerular deposition of immune complexes. When mice with genetically disrupted NOS2 were backcrossed to MRL-lpr/lpr mice, the resultant - / - mice expressed no NOS2 and produced no NO, the wild-type +/+ mice overexpressed NOS2 and overproduced NO (in comparison to normal, control mice), and the heterozygous + /- mice expressed and produced intermediate levels. Nephritis and arthritis in the - / - mice were comparable to that in MRL-lpr/lpr mice, but vasculitis was markedly decreased. Levels of anti-DNA antibodies were comparable in all mice,
but IgG rheumatoid factor production was markedly reduced in the - / - mice. These results of studies in MRL-Iprllpr mice with genetically disrupted NOS2 highlight the heterogeneity and complexity of the role NOS2 and NO in inflam mation. Further studies in animal models and in humans with inflammatory dis eases such as rheumatoid arthritis may lead to the development of novel thera pies targeting NOS and NO.
