Selective Inhibition of Inducible Nitric Oxide Synthase Exacerbates Erosive Joint Disease

Abstract

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 NG-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.

Exposure to a Dysfunctional Glucocorticoid Receptor from Early Embryonic Life Programs the Resistance to Experimental Autoimmune Encephalomyelitis Via Nitric Oxide-Induced Immunosuppression

“…Alternatively, L-NIL (3 mg/kg) was administrated i.p. daily (48). Comparison between oral and i.p delivery of inhibitors yielded similar levels of inhibition of NO production.…”

“…In a second study the specific iNOS inhibitor, L-NIL, was added to the drinking water (100 g/ml) (19, 48) 0 -1 days after immunization for 8 consecutive days. Solutions were prepared daily, fluid consumption in both L-NIL-treated and untreated mice was monitored due to changes in water consumption during the development of disease symptoms, and doses of L-NIL were adjusted accordingly (48). Alternatively, L-NIL (3 mg/kg) was administrated i.p.…”

“…Since iNOS/NO is known to inhibit proliferation of different cell types (20, 21, 46, 50 -52), we investigated whether the GR deficiency of Tg mice influences endogenous NO, by application of L-NAME and L-NMMA or the specific iNOS inhibitor, L-NIL (45,48). It was observed that both Tg-CM (Fig.…”

Nitric oxide: a key regulator of myeloid inflammatory cell apoptosis

“…Although iNOS has been implicated in the pathogenesis of certain inflammatory diseases, such as arthritis, SLE and irritable bowel syndrome, 62 a number of studies have demonstrated a protective effect of NO against several conditions characterised by inflammation, such as glomerulonephritis, 63 acute hepatic necrosis, 64 arthritis, 65,66 endotoxaemia 64 and acute lung injury 67 in vivo (reviewed by Clancy and Abramson 62 ). Most studies attribute these effects to the wide range of general anti-inflammatory properties of NO, as reviewed by Granger and Kubes, 9 and are outwith the scope of this review.…”

Apoptotic Programs Are Determined during Lineage Commitment of CD4+ T Effectors: Selective Regulation of T Effector-Memory Apoptosis by Inducible Nitric Oxide Synthase

“…Naive OT-II transgenic T cells, transferred to congenic hosts, were challenged with mOVA, accompanied by continued (daily) injections of the inhibitors 1400W (16) or L-NIL (17) or the vehicle control. Cell recoveries were assessed in circulation of immunized mice on days 4 and 14 after the first challenge.…”