Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation.
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 E(2) (PGE(2)) 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 PGE(2) levels, joint swelling was significantly exacerbated in this model. Co-administration of the inhibitors nullified the benefits of SC-236.


CONCLUSIONS
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.
Day
S M
SM
Biological Sciences, University of Paisley, Paisley PA1 2BE, Scotland, UK.
Lockhart
J C
JC
Ferrell
W R
WR
McLean
J S
JS
D000208:Acute Disease; D000818:Animals; D001169:Arthritis, Experimental / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control; D002351:Carrageenan; D002908:Chronic Disease; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000627:therapeutic use; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008239:Lysine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D008297:Male; D009569:Nitric Oxide / Q000502:physiology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors / Q000502:physiology; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins / Q000502:physiology*; D011720:Pyrazoles / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D013449:Sulfonamides / Q000627:therapeutic use; D000096926:Benzenesulfonamides
D002351:Carrageenan; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D008239:Lysine; D009569:Nitric Oxide; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D011451:Prostaglandin-Endoperoxide Synthases; D011453:Prostaglandins; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C090663:N(6)-(1-iminoethyl)lysine; C496318:Nos2 protein, rat