Exacerbation of antigen-induced arthritis in inducible nitric oxide synthase-deficient mice.
OBJECTIVE
Inhibition of nitric oxide (NO) produced by inducible NO synthase (iNOS) is suggested to be beneficial in experimental arthritis. Although NO is important for the integrity of the microcirculation, the effects of inhibition of iNOS on the synovial microcirculation are not currently known. This study investigated the synovial microcirculation and leukocyte-endothelial cell interactions in iNOS-deficient mice with antigen-induced arthritis (AIA) and compared these findings with disease severity.


METHODS
Fourteen homozygous iNOS-/- and 14 iNOS+/+ mice were used. The severity of AIA was assessed by measuring knee joint swelling and by histologic scoring. The number of rolling and adherent leukocytes was quantitatively analyzed in synovial microvessels using intravital microscopy of intraarticular synovial tissue. Nitrite/nitrate concentrations were measured, and the expression of iNOS, E- and P-selectin, intercellular adhesion molecule 1, and vascular cell adhesion molecule 1 (VCAM-1) was assessed by immunohistochemistry.


RESULTS
In iNOS+/+ animals with AIA, the plasma concentration of nitrite/nitrate was increased 3-fold and iNOS expression was detected in cells of the joint. Swelling of the knee joint as well as leukocyte infiltration were enhanced in the iNOS-/- arthritic animals compared with iNOS+/+ mice with AIA. AIA-associated leukocyte-endothelial cell interaction in synovial postcapillary venules was more pronounced in iNOS-/-, compared with iNOS+/+, arthritic mice. A strong expression of P-selectin and VCAM-1 was observed in the iNOS-/- arthritic mice only.


CONCLUSIONS
These data suggest that NO production by iNOS in vivo has antiinflammatory effects in experimental arthritis, by mediating a reduction in leukocyte adhesion and infiltration.
Veihelmann
A
A
Department of Orthopedics, Ludwig-Maximilians-University of Munich, Germany.
Landes
J
J
Hofbauer
A
A
Dorger
M
M
Refior
H J
HJ
Messmer
K
K
Krombach
F
F
D000818:Animals; D001169:Arthritis, Experimental / Q000097:blood / Q000201:enzymology* / Q000473:pathology; D019040:E-Selectin / Q000378:metabolism; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008833:Microcirculation / Q000473:pathology; D008856:Microscopy, Fluorescence; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000096:biosynthesis* / Q000172:deficiency / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D009573:Nitrites / Q000097:blood; D019007:P-Selectin / Q000378:metabolism; D013264:Stifle / Q000378:metabolism / Q000473:pathology; D013583:Synovial Membrane / Q000098:blood supply / Q000473:pathology; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D019040:E-Selectin; D009566:Nitrates; D009573:Nitrites; D019007:P-Selectin; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; C496317:Nos2 protein, mouse