Divergent roles of nitrergic and prostanoid pathways in chronic joint inflammation

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 (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. 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.

The Arthritis Severity Quantitative Trait Loci Cia4 and Cia6 Regulate Neutrophil Migration into Inflammatory Sites and Levels of TNF-α and Nitric Oxide

“…NO can also induce neutrophil apoptosis (54). NO inhibitors upregulate the expression of adhesion molecules and exacerbate several models of inflammation (54,56), including chronic arthritis (57). There is evidence for a strong genetic contribution to the regulation of levels of NO in humans (58), but this is the first study to identify a QTL that regulates these levels.…”

Interdicting protease-activated receptor-2-driven inflammation with cell-penetrating pepducins

“…Acute inflammatory edema was induced by an intraplantar injection of λ-carrageenan and kaolin, irritants that cause a massive leukocytosis and hyperemic response, which leads to localized swelling (32). We also directly assessed the PAR2-dependent activity of P2pal-18S by quantifying its inhibitory effects against the PAR2-specific agonist SLIGRL when injected into the hind footpad of WT C57BL/6 mice.…”

Can l(+)-lactate be used as a marker of experimentally induced inflammation in rats?

“…Prostaglandins are produced following the sequential oxidation of arachidonic acid, gamma-linolenic acid or eicosapentaenoic acid by cyclooxygenases and terminal prostaglandin synthases [1][2][3]. One of the key mediators/markers of the inflammatory process is PGE 2 [4][5][6][7], which is generated by the action of prostaglandin E synthases on prostaglandin H 2 . Non-steroidal antiinflammatory drugs that inhibit COX pathways and thereby the synthesis of PGE 2 are commonly used in the treatment of joint inflammation [8][9][10].…”