ANTI-INFLAMMATORY EFFECTS OF NITRIC OXIDE IN ANTIGEN-INDUCED ARTHRITIS: A STUDY ON INOS-DEFICIENT MICE

Nitric oxide (NO) production by the inducible NO synthase (iNOS) and enhanced emigration of leukocytes into synovial tissue are suggested to play a crucial role in mediating chronic joint inflammation such as rheumatoid arthritis. The effects of iNOS inhibition in experimental arthritis are dicussed controversally. The aim of our study was to analyze the synovial microcirculation and leukocyte endothelial cell interactions in iNOS-deficient mice with antigen-induced arthritis (AiA) in vivo. 14 homocygote iNOS-deficient (iNOS KO C57BL6/J x 129SvEv; Merck & Co., Rahway, NJ, USA) and 14 iNOS-positive (C57BL6/J x 129SvEv) mice were used for our study. The patella tendon was resected, which allows for visualization of the intraarticular synovial tissue of the knee joint using intravital fluorescence microscopy. Animals were allocated into four groups (iNOS +/+, iNOS +/+ with AiA, iNOS −/− and iNOS −/− with AiA) (n=7 each group). On day 8 after arthritis induction, functional capillary density (FCD), fraction of rolling leukocytes, and the number of adherent leukocytes were quantitatively analyzed in synovial postcapillary venules. Histologic sections were performed to assess leukocyte infiltration of the synovium. FCD or leukocyte-endothelial cell interaction were not altered in healthy iNOS-deficient mice in comparison to iNOS +/+ animals. However, in iNOS-deficient animals with AiA there was a significant increase in the fraction of rolling (0,510,05) and in the number of adherent leukocytes (729126 mm-2) in comparison to wild type mice with AiA (0,330,07 and 565110 mm-2) (MWSEM, p In our study, there was an enhanced leukocyte accumulation and extravasation in iNOS-deficient mice with antigen-induced arthritis in comparison to iNOS-positive animals with arthritis. Thus, the induction of iNOS appears as critical protective response to AiA possibly by reducing leukocyte adhesion and infiltration.