Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease.
NO is an essential cytotoxic agent in host defense, yet can be autotoxic if overproduced, as evidenced in inflammatory lesions and tissue destruction in experimental arthritis models. Treatment of streptococcal cell wal1-induced arthritis in rats with N:(G)-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO synthase (NOS), prevents intraarticular accumulation of leukocytes, joint swelling, and bone erosion. Because increased inducible NOS (iNOS) expression and NO generation are associated with pathogenesis of chronic inflammation, we investigated whether a selective inhibitor of iNOS, N:-iminoethyl-L-lysine (L-NIL), would have more directed anti-arthritic properties. Whereas both L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall-stimulated rat mononuclear cells in vitro and systemic treatment of arthritic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate resolution of inflammatory joint lesions. On the contrary, daily administration of L-NIL failed to reduce the acute response and exacerbated the chronic inflammatory response, as reflected by profound tissue destruction and loss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NIL, immunohistochemical analyses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NIL treatment. These studies uncover a contribution of the constitutive isoforms of NOS to the evolution of acute and chronic inflammation pathology which may be important in the design of therapeutic agents.
McCartney-Francis
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NL
Oral Infection and Immunity Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA.
Song
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Mizel
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Wahl
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SM
D000284:Administration, Oral; D000818:Animals; D001169:Arthritis, Experimental / Q000201:enzymology* / Q000473:pathology* / Q000517:prevention & control; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006614:Hindlimb; D007274:Injections, Intraperitoneal; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D007964:Leukocytosis / Q000201:enzymology / Q000473:pathology / Q000517:prevention & control; D008239:Lysine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D009504:Neutrophils / Q000201:enzymology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors* / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D052247:Nitric Oxide Synthase Type II; D011135:Polysaccharides, Bacterial / Q000008:administration & dosage; D051381:Rats; D011917:Rats, Inbred Lew; D019323:omega-N-Methylarginine / Q000008:administration & dosage / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007527:Isoenzymes; C090663:N(6)-(1-iminoethyl)lysine; D011135:Polysaccharides, Bacterial; C102511:cell wall polysaccharide, Streptococcus; D019323:omega-N-Methylarginine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat; D008239:Lysine