THE ROLE OF NITRIC-OXIDE IN THE PATHOGENESIS OF SPONTANEOUS MURINE AUTOIMMUNE-DISEASE - INCREASED NITRIC-OXIDE PRODUCTION AND NITRIC-OXIDE SYNTHASE EXPRESSION IN MRL-LPR LPR MICE, AND REDUCTION OF SPONTANEOUS GLOMERULONEPHRITIS AND ARTHRITIS BY ORALLY-ADMINISTERED N-G-MONOMETHYL-L-ARGININE/

MRL-lpr/lpr mice spontaneously develop various manifestations of autoi mmunity including an inflammatory arthropathy and immune complex glome rulonephritis. This study examines the role of nitric oxide, a molecul e with proinflammatory actions, in the pathogenesis of MRL-lpr/lpr aut oimmune disease. MRL-lpr/lpr mice excreted more urinary nitrite/nitrat e (an in vivo marker of nitric oxide production) than did mice of norm al strains and MRL-+/+ and B6-lpr/lpr congenic strains. In addition, M RL-lpr/lpr peritoneal macrophages had an enhanced capacity to produce nitric oxide in vitro as well as increased nitric oxide synthase activ ity, and certain tissues from MRL-lpr/lpr mice had increased expressio n of inducible nitric oxide synthase (NOS) mRNA and increased amounts of material immunoreactive for inducible NOS. Oral administration of N -G-monomethyl-L-arginine, a nitric oxide synthase inhibitor, prevented the development of glomerulonephritis and reduced the intensity of in flammatory arthritis in MRL-lpr/lpr mice. By using interspecific backc ross mice, the gene for inducible NOS (Nosi) was mapped to mouse chrom osome 11. This chromosomal localization was different from those loci that we have previously demonstrated to be linked to enhanced suscepti bility to renal disease in an MRL-lpr/lpr cross. However, the chromoso mal location of the NOS gene was consistent with an insulin-dependent diabetes locus identified in an analysis of nonobese diabetic (NOD) mi ce. 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.