The objective of this research program is to define the phenotypic and functional properties of monocytes and the molecular mechanisms that regulate the inflammatory process. One effector molecule that has been implicated as a mediator of immune and inflammatory responses is nitric oxide (NO), a toxic radical gas produced during the metabolisn of L- arginine by NO synthase (NOS). Previous studies have identified increased levels of nitric oxide in synvovial fluids from rheumatoid arthritis patients. These studies provided evidence that nitrogen intermediates might contribute to pathologic sequelae in chronically inflamed tissue. A single injection of streptococcal cell walls (SCW) induces the accumulation of inflammatory cells within the synovial tissue and a cell-mediated immune response that leads to destructive lesions. NO production is elevated in the inflamed joints of SCW-treated rats. To address the possible therapeutic intervention of the nitric oxide pathway, arthritic rats were treated with daily injections of NG- monomethyl-L-arginine, an analog of arginine and inhibitor of NOS. NMMA profoundly reduced the synovial inflammation and tissue damage, implicating the NO pathway in the pathogenesis of inflammatory arthritis and demonstrating the ability of a NOS inhibitor to modulate the disease. Elevated nitrite levels have also been demonstrated in other inflammatory and infectious diseases such as periodontal disease and AIDS, suggesting that NOS inhibitors may be useful in the diagnosis and treatment of these and other inflammatory and immune mediated disorders.
