Suppression of adjuvant arthritis and synovial macrophage inducible nitric oxide by N-iminoethyl-L-ornithine, a nitric oxide synthase inhibitor.
Nitric oxide (NO.) is a pro-inflammatory effector molecule in certain inflammatory diseases, including arthritis. We investigated the production of NO. by adjuvant arthritis (AA) synovial macrophages, and studied the effects of a NO. synthase inhibitor. N-iminoethyl-L-ornithine (L-NIO). Compared to control rats, rats treated with L-NIO in vivo exhibited significantly lower articular index (p < 0.05), paw volume (p < 0.05), and synovial fluid cell count (p < 0.05). No effect on cutaneous delayed-type hypersensitivity to the disease-initiating antigen was observed. Inducible NO. synthase (iNOS) was detected in AA synovial macrophages, and cultured AA synovial macrophage iNOS levels were increased by a factor of 138 +/- 17% (p < 0.01) by 1 microgram/ml LPS in vitro. Constitutive NO. production by AA synovial macrophages (43 +/- 1 nmol/10(5) cells/24 h) was significantly inhibited by 10 nM L-NIO in vitro (32 +/- 0.5, p < 0.01). NO. production induced by 1 microgram/ml LPS (48 +/- 2) was also decreased by L-NIO (39 +/- 2, p < 0.05). In vivo L-NIO treatment also inhibited alveolar macrophage NO. production (p < 0.05). The ability of L-NIO to decrease iNOS-mediated synovial macrophage NO. production and inhibit the clinical parameters of AA implicate macrophage-derived NO. in the pathogenesis of this disease.
Santos
L L
LL
Centre for Inflammatory Diseases, Monash Medical Centre, Australia.
Morand
E F
EF
Yang
Y
Y
Hutchinson
P
P
Holdsworth
S R
SR
D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006968:Hypersensitivity, Delayed; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D009569:Nitric Oxide / Q000096:biosynthesis*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009952:Ornithine / Q000031:analogs & derivatives* / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012867:Skin / Q000187:drug effects / Q000276:immunology; D013583:Synovial Membrane / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology
D004791:Enzyme Inhibitors; D018836:Inflammation Mediators; D009569:Nitric Oxide; C065027:N(G)-iminoethylornithine; D009952:Ornithine; D019001:Nitric Oxide Synthase