SummaryThe contribution of reactive oxygen species (ROS), in particular hydroxyl radical (OH •), to joint inflammation was examined in rats developing adjuvant arthritis (AA) by treatment with ROS scavengers dimethylthiourea (DMTU) and DMSO. Adjuvant arthritis was induced in Sprague-Dawiey (SD) rats by a single intradermal (i.d.) injection o'i Mycobacteriwn tuhcrctilosis (MT) in oil on day 0. By day 14, all rats exhibited arthritis in the hindlimbs and the majority had involvement of the forelimbs. A marked inflammatory cell influx (75% neutrophils) was present in the synovial fluid. These cells, in vitro, spontaneously produced OH-{0.96±0.28 OH-units/h per 10-cells). In contrast, spontaneous OH-production by normal circulating leucocytes was absent (0.07±0.03 OH-units/h per 10^ cells). Adjuvant-injected rats were treated with DMTU (500, 250 and 100 mg/kg). DMSO (330 and 165 mg/ kg) or saline (disease control) once daily on days 8, 9 and 10 and twice daily on days 1 1. 12 and 13 postadjuvant injection. Both DMTU and DMSO significantly reduced the clinical evidence of arthritis ells/four joints, /"< 0.01 compared with disease control = 11.76 ± 1.7 x 10^ cells/four joints). Neither treatment inhibited cutaneous delayed type hypersensitivity (DTH) to the disease inducing antigen. Furthermore, DMTU (500 mg/kg) did not cause neutropenia nor inhibit peritoneal neutrophil accumulation in response to a chemotactic stimulus. This study demonstrates the attenuation of adjuvant arthritis by ROS scavengers and suggests a pivotal role for ROS, particularly 0H-, in the mediation of joint inflammation in this disease.

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The effect of cyclosporin A (C YA) on the development of active and passive modeis of rat anti-glomerular basement membrane antibody-induced glomerulonephritis (anti-GBM-GN) was assessed. Active GN was induced by an intravenous injection of sheep anti-rat GBM globulin to preimmunized rats. After 5 days, a diffuse proliferative GN with proteinuria and linear GBM deposition of rat IgG was regularly observed. CYA treatment, commencing prior to preimmunization, significantly attenuated the glomerular lesion, reduced proteinuria, prevented linear deposition of rat IgG and reduced the serum titre of anti-sheep globulin antibody. However, treatment started after the antibody response was established failed to alter antibody production, its glomerular deposition or the outcome of the disease. CYA treatment did not effect passive anti-GBM-GN, occurring 24 h after intravenous administration of sheep anti-rat GBM globulin to unimmunized rats. Thus, CYA is able to block anti-GBM-GN when given prior to induction of disease, by preventing an active antibody response. However, it did not alter GN when the antibody response was well established, or when glomerular injury was passively induced.