Exacerbation of antigen-induced arthritis in inducible nitric oxide synthase-deficient mice

Objective. Inhibition of nitric oxide (NO) produced by inducible NO synthas e (iNOS) is suggested to be beneficial in experimental arthritis. Although NO is important for the integrity of the microcirculation, the effects of i nhibition of MOS on the synovial microcirculation are not currently known. This study investigated the synovial microcirculation and leukocyte-endothe lial cell interactions in iNOS-deficient mice with antigen-induced arthriti s (AIA) and compared these findings with disease severity. Methods. Fourteen homozygous iNOS-/- and 14 iNOS+/+ mice were used. The sev erity of AIA was assessed by measuring knee joint swelling and by histologi c scoring. The number of rolling and adherent leukocytes was quantitatively analyzed in synovial microvessels using intravital microscopy of intraarti cular synovial tissue. Nitrite/nitrate concentrations were measured, and th e expression of iNOS, E- and P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 (VCAM-1) was assessed by immunohisto chemistry. Results. In iNOS+/+ animals with AIA, the plasma concentration of nitrite/n itrate was increased 3-fold and MOS expression was detected in cells of the joint. Swelling of the knee joint as well as leukocyte infiltration were e nhanced in the iNOS-/- arthritic animals compared with iNOS+/+ mice with AI A. AIA-associated leukocyte-endothelial cell interaction in synovial postca pillary venules was more pronounced in iNOS-/-, compared with iNOS+/+, arth ritic mice. A strong expression of P-selectin and VCAM-1 was observed in th e iNOS-/- arthritic mice only. Conclusion. These data suggest that NO production by iNOS in vivo has antii nflammatory effects in experimental arthritis, by mediating a reduction in leukocyte adhesion and infiltration.