EXTENDED REPORT

Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation

S M Day¹, J C Lockhart¹, W R Ferrell², J S McLean¹

¹ Biological Sciences, University of Paisley, Paisley PA1 2BE, Scotland, UK
² Centre for Rheumatic Diseases, Royal Infirmary, Glasgow G31 2ER, Scotland, UK

Correspondence to:
Correspondence to:
Professor J C Lockhart
Biological Sciences, University of Paisley, Paisley PA1 2BE, Scotland, UK; john.lockhart{at}paisley.ac.uk

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 (NO_x), 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 NO_x 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.

Abbreviations: 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, N^G-monomethyl-L-arginine; L-NAME, N^w-nitro-L-arginine; LPS, lipopolysaccharide; NO_x, nitric oxide metabolites; PGE₂, prostaglandin E₂; RA, rheumatoid arthritis; TNF, tumour necrosis factor

Keywords: nitric oxide; prostaglandin E2; L-NIL; SC-236; adjuvant induced arthritis; carrageenan

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