The effects of Celecoxib on inflammation and synovial microcirculation in murine antigen-induced arthritis

H.H. Gebhard^1*, S.P. Zysk^2*, M. Schmitt-Sody², V. Jansson², K. Messmer¹, A. Veihelmann²

¹Institute for Surgical Research, Ludwig-Maximilians University of Munich; ²Department of Orthopaedics, Klinikum Grosshadern, Ludwig-Maximilians University of Munich, Germany.

ABSTRACT
Objective
There is controversy about the effects of cyclooxygenase-2 (COX-2) on adhesion molecules and the microvasculature in inflamed tissue. Thus, the aim of this study was to assess COX-2-expression in Antigen-induced Arthritis (AiA) and to investigate the effects of selective COX-2 inhibition by Celecoxib (4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl] benzenesulfonamide) (CXB), on synovial microcirculation and adhesion molecule expression in arthritic as well as healthy mice.

Methods
Balb/c mice were allocated to 4 groups; 2 control groups with saline or CXB and 2 groups with AiA which also received saline or CXB (30 mg/kg BW in 0.3 ml solution). The severity of arthritis was assessed by changes in the transverse joint diameter. On day 14 after AiA-induction, the patella tendon of the left knee joint was microsurgically resected and intravital fluorescence microscopy on synovial tissue was performed. Finally, the knee joint was removed for histology and immunohistochmistry.

Results
COX-2-expression in the inflamed synovium was demonstrated by immunohistochemistry. Application of Celecoxib resulted in a significant reduction in the rolling leukocyte fraction as well as in the number of leukocytes adherent to the endothelium (0.25 ± 0.1 and 96 ± 34 cells/mm² respectively) in comparison to the untreated animals with AiA (0.44 ± 0.03 and 206 ± 22 cells/mm² respectively). Additionally, CXB-treated arthritic animals showed significantly less knee joint swelling and reduced adhesion molecule expression.

Conclusion
In the present study, COX-2 expression in the synovial tissue of mice with AiA could be demonstrated. Selective COX-2 inhibition with CXB resulted in reduced leucocyte-endothelial cell interactions and decreased adhesion molecule expression. Evidence for a protective role of COX-2 in mouse AiA was not found.

Key words
Cyclooxygenase 2, antigen-induced arthritis, celecoxib, adhesion molecules, intravital microscopy.

*Both of these authors contributed equally to the study.
This work was supported by a grant from Pfizer GmbH, Karlsruhe, Germany.
Please address correspondence and re-print requests to: Dr. med. Stefan P. Zysk, Department of Orthopaedics, Ludwig Maximilians University, Klinikum Grobhadern, Marchioninistrasse 15, D-81377 Munich, Germany.
E-mail: szysk@med.uni-muenchen.de

Clin Exp Rheumatol 2005; 23: 63-70.
© CLINICAL AND EXPERIMENTAL RHEUMATOLOGY 2005.