NITRIC-OXIDE PRODUCTION IN RELATION TO SPONTANEOUS B-CELL LYMPHOMA AND MYOSITIS IN SJL MICE

SJL mice spontaneously develop B cell lymphomas (historically describe d as reticulum cell sarcomas) by 12 months of age and inflammatory mus cle disease (myositis) by 6 months of age. Tumors originate in mesente ric lymph nodes and in Peyer's patches and resemble human germinal cen ter lymphomas. The growth of reticulum cell sarcomas is completely dep endent on cytokine production by normal T cells, The spontaneous myosi tis, which resembles human idiopathic myositis, is characterized by va rious abnormalities in skeletal muscle, including infiltration with in flammatory cells consisting primarily of macrophages. The participatio n of different cytokines in the pathogenesis of the lymphoma and the m assive invasion of macrophages into muscle tissues led us to investiga te the possible involvement of nitric oxide (NO .), which is known to be synthesized by activated macrophages under inflammatory conditions. Elevated NO . production, measured by urinary nitrate excretion, by S JL mice in comparison with BALB/c control mice was observed as early a s 7 weeks of age, Both aging and degree of spontaneous myositis correl ated with increased nitric oxide production. Oral administration of N- monomethyl-L-arginine, an inhibitor of nitric oxide synthase (NOS), re duced urinary nitrate excretion and also the severity of myositis. Imm unohistochemical analysis revealed the presence of inducible NOS (iNOS ) in cells in the spleen, lymph nodes, and skeletal muscle. The iNOS i s primarily responsible for the enhanced nitric oxide production, Morp hology of cells that stained positive for iNOS was similar to that of macrophages infiltrating into the affected tissues, Chronic production of elevated amounts of nitric oxide by the SJL mice, therefore, provi des a useful in vivo model for future studies of cellular damage resul ting from endogenously produced NO . in combination with oxygen radica ls,