IMMUNOLOGICAL ABNORMALITY ASSOCIATED WITH THE AUGMENTED NITRIC-OXIDE SYNTHESIS IN ADJUVANT-INDUCED ARTHRITIS

Excessive nitric oxide (NO) synthesis by inducible NO synthase (iNOS), has been implicated in the pathogenesis of inflammatory diseases such as rheumatoid arthritis. We investigated the pathophysiological role of NO using an adjuvant-induced arthritis model. Kinetics of iNOS mRNA expression in paw and spleen showed that it was induced from an early stage of the disease. To further characterize the pathophysiological relevance of iNOS induction in spleen, the mitogenic response of splee n cells was examined. ConA-induced proliferation of spleen cells from arthritic rats was completely suppressed in comparison to normal fats. Elevation of nitrite, which could be converted from NO, was also obse rved in the culture supernatants. Addition of three NOS inhibitors, S- (2-aminoethyl) isothiouronium bromide (ITU), aminoguanidine (AG) and L NG-nitroarginine methyl ester (L-NAME) all reduced the nitrite level a nd restored the proliferative response dose-dependently. These NOS inh ibitors also showed anti-arthritic effects. Daily subcutaneous adminis tration of either ITU at 50 mg/kg or AG at 200 mg/kg suppressed the pa w swelling by 50% in arthritic rats on day 18. Oral administration of L-NAME at 30 mg/kg showed a tendency to suppress the development of ar thritis from day ii to day 15. However, drug-induced hypertension was observed with L-NAME due to poor selectivity for iNOS isozyme. These r esults suggest that augmented NO synthesis, via iNOS induction, may be partly involved in the pathogenesis of adjuvant-induced arthritis by causing defects in lymphocyte function. Thus, selective inhibition of iNOS might be beneficial for the treatment of immunological abnormalit ies associated with inflammatory diseases. (C) 1998 International Soci ety for Immunopharmacology. Published by Elsevier Science Ltd. All rig hts reserved.