Induction of arthritis in mice and rats by potassium peroxochromate and assessment of disease activity by whole blood chemiluminescence and 99mpertechnetate-imaging.

Abstract

Arthritis develops in DBA/1xB10A(4R) mice and Wistar rats upon intraplantar injection of potassium peroxochromate (K3CrO8), and is here quantified by whole blood chemiluminescence (CL) and 99mpertechnetate-imaging (99mTcO4-), and related to overt disease symptoms (the arthritis index). During the aqueous decay of K3CrO8 to chromate (VI), the chromium(V)-bound oxygen is released as superoxide, hydroxyl radicals, singlet oxygen and hydrogen peroxide, the same reactants, which are produced by activated phagocytes during inflammation. Reactive oxygen species (ROS) trigger the breakdown of the sulfhydryl-dependent antioxidant defence system and induce the nuclear factor kappa B-dependent expression of pro-inflammatory cytokines, which prime phagocytic NADPH oxidases to the enhanced production of ROS. During both the acute inflammatory response and the onset of the secondary response in non-injected paws, the phorbolester-stimulated ROS production of phagocytes was significantly enhanced (p < 0.001) and correlated well to the arthritis index (r = 0.797) and the uptake of 99mTcO4- into inflamed joints. Chromate(VI), formed during the decay of K3CrO8, contributes to the progression of arthritis by inhibition of glutathione reductase, thereby increasing intracellular H2O2 concentrations. In addition, Cr(VI) reduced 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 primary response into chronic self-perpetuating inflammation. We see the main application of K3CrO8-induced arthritis and its assessment by both 99mTcO4- imaging and chemiluminescent immunosensoring of phagocytic activity in unseparated blood as for the rapid screening of novel anti-rheumatic drugs and treatments.