Selective inhibition of inducible nitric oxide synthase exacerbates erosive joint disease

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 wall-indu ced arthritis in rats with NG-monomethyl-L-arginine (L-NMMA), a competitive nonspecific inhibitor of both constitutive and inducible isoforms of NO sy nthase (NOS), prevents intraarticular accumulation of leukocytes, joint swe lling, 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-lysi ne (L-NIL), would have more directed anti-arthritic properties. Whereas bot h L-NMMA and L-NIL inhibited nitrite production by streptococcal cell wall- stimulated rat mononuclear cells;in vitro and systemic treatment of arthrit ic rats with L-NMMA ablated synovitis, surprisingly L-NIL did not mediate r esolution of inflammatory joint lesions. On the contrary; daily administrat ion of L-NIL failed to reduce the acute response and exacerbated the chroni c inflammatory response, as reflected by profound tissue destruction and lo ss of bone and cartilage. Although the number of iNOS-positive cells within the synovium decreased after treatment with L-NB, immunohistochemical anal yses revealed a distinct pattern of endothelial and neuronal NOS expression in the arthritic synovium that was unaffected by the isoform-specific L-NI L treatment. These studies uncover a contribution of the constitutive isofo rms of NOS to the evolution of acute and chronic inflammation pathology whi ch may be important in the design of therapeutic agents.