INDUCTION OF ARTHRITIS IN MICE AND RATS BY POTASSIUM PEROXOCHROMATE AND ASSESSMENT OF DISEASE-ACTIVITY BY WHOLE-BLOOD CHEMILUMINESCENCE AND(99M)PERTECHNETATE-IMAGING

Arthritis develops in DBA/1xB10A(4R) mice and Wistar rats upon intrapl antar injection of potassium peroxochromate (K3CrO8), and is here quan tified by whole blood chemiluminescence (CL) and (99m)pertechnetate-im aging((TCO4-)-T-99m) and related to overt disease symptoms (the arthri tis index). During the aqueous decay of K3CrO8 to chromate (VI), the c hromium(V)-bound oxygen is released as superoxide, hydroxylradicals, s inglet oxygen and hydrogen peroxide, the same reactants, which are pro duced by activated phagocytes during inflammation. Reactive oxygen spe cies (ROS) trigger the breakdown of the sulfhydryl-dependent antioxida nt defence system and induce the nuclear factor kappa B-dependent expr ession of pro-inflammatory cytokines, which prime phagocytic NADPH oxi dases to the enhanced production of ROS. During both the acute inflamm atory response and the onset of the secondary response in non-injected paws, the phorbolester-stimulated ROS production of phagocytes was si gnificantly enhanced (p < 0.001) and correlated well to the arthritis index (r = 0.797) and the uptake of (TCO4-)-T-99m into inflamed joints . Chromate(VI), formed during the decay of K3CrO8, contributes to the progression of arthritis by inhibition of glutathione reductase, there by increasing intracellular H2O2 concentrations. In addition, Cr(VI) r educed to Cr(V) by ascorbate, catalyzes hydroxyl radical production in the presence of hydrogen peroxide. A stable loop forms, in which ROS, continuously produced by Cr(VI)/Cr(V) redox-cycling, drive the primar y response into chronic self-perpetuating inflammation. We see the mai n application of K3CrO8-induced arthritis and its assessment by both ( TCO4-)-T-99m Imaging and chemiluminescent immunosensoring of phagocyti c activity in unseparated blood as for the rapid screening of novel an ti-rheumatic drugs and treatments.