Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation. Issue 12 (16th November 2004)

• Record Type: Journal Article
• Authors: Day, S M; Lockhart, J C; Ferrell, W R; McLean, J S
• Is Part Of: Annals of the rheumatic diseases. Volume 63:Issue 12(2004)
• Page Start: 1564
• Page End: 1570
• Publication Date: 2004-11-16
• Subjects: ANOVA, analysis of variance -- C/K, 2% carrageenan/4% kaolin -- COX, cyclo-oxygenase -- ELISA, enzyme linked immunosorbent assay -- IC50, 50% inhibitory concentration -- iNOS, inducible nitric oxide synthase -- l-NIL, (l-N-(1-iminoethyl)-lysine -- l-NMMA, NG-monomethyl-l-arginine -- l-NAME, Nw-nitro-l-arginine -- LPS, lipopolysaccharide -- NOx, nitric oxide metabolites -- PGE2, prostaglandin E2 -- RA, rheumatoid arthritis -- TNFα, tumour necrosis factor α; nitric oxide -- prostaglandin E2 -- L-NIL -- SC-236 -- adjuvant induced arthritis -- carrageenan; Rheumatism -- Periodicals; 616.723005
• DOI: 10.1136/ard.2003.017269
• Languages: English
• ISSNs: 0003-4967

Abstract

Abstract : Background: Nitrergic and prostanoid pathways have both been implicated in inflammatory processes. Objective: To investigate their respective contributions in a rat model of chronic arthritis. Methods: Male Wistar rats (n = 4–6/group) received either an intra-articular injection of 2% carrageenan/4% kaolin (C/K) or intra- and periarticular injections of Freund's complete adjuvant (FCA; 10 mg/ml M tuberculosis ). Joint diameter, urinary nitric oxide metabolites (NOx ), and prostaglandin E2 (PGE2 ) levels were measured as indices of the inflammatory process. A prophylactic and therapeutic (day 5) dose ranging study of an inducible nitric oxide synthase inhibitor, l - N -(1-iminoethyl)-lysine (l -NIL), and a cyclo-oxygenase-2 (COX-2) inhibitor, SC-236, was performed with the drugs given subcutaneously. Submaximal doses were identified and used for combination studies. Appropriate vehicle controls were included. Results: l -NIL and SC-236 dose dependently inhibited C/K induced acute joint swelling, the magnitude being greatest when they were given in combination. Both prophylactic and therapeutic administration of SC-236 in the FCA induced model of chronic arthritis produced a dose dependent reduction in all the measures assessed. However, although l -NIL demonstrated similar dose dependent inhibition of urinary NOx and PGE2 levels, joint swelling was significantly exacerbated in this model. Co-administration of the inhibitors nullified the benefits of SC-236. Conclusion: Whereas COX-2 derived prostaglandins are proinflammatory in both acute and chronic joint inflammation, NO seems to have divergent roles, being anti-inflammatory in chronic and proinflammatory in acute joint inflammation.