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 spleen cells was examined. ConA-induced proliferation of spleen cells from arthritic rats was completely suppressed in comparison to normal rats. Elevation of nitrite, which could be converted from NO, was also observed in the culture supernatants. Addition of three NOS inhibitors, S-(2-aminoethyl) isothiouronium bromide (ITU), aminoguanidine (AG) and LNG-nitroarginine methyl ester (L-NAME) all reduced the nitrite level and restored the proliferative response dose-dependently. These NOS inhibitors also showed anti-arthritic effects. Daily subcutaneous administration of either ITU at 50 mg/kg or AG at 200 mg/kg suppressed the paw 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 arthritis from day 11 to day 15. However, drug-induced hypertension was observed with L-NAME due to poor selectivity for iNOS isozyme. These results 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 abnormalities associated with inflammatory diseases.
Tanaka
S
S
Lead Generation Research Laboratory, Tanabe Seiyaku Co. Ltd, Osaka, Japan.
Matsui
T
T
Murakami
T
T
Ishizuka
T
T
Sugiura
M
M
Kawashima
K
K
Sugita
T
T
D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000276:immunology* / Q000378:metabolism*; D003208:Concanavalin A / Q000494:pharmacology; D004790:Enzyme Induction; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D008213:Lymphocyte Activation / Q000187:drug effects; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D051381:Rats; D011917:Rats, Inbred Lew; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000276:immunology
D004791:Enzyme Inhibitors; D003208:Concanavalin A; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat