Murine models of chronic inflammation

Abstract

Acute rodent models such as the carrageenan edema and the ultraviolet light edema tests of inflammation, and the phenylbenzoquinone writhing test of analgesia have been instrumental in the discovery and development of nonsteroidal antiinflammatory drugs (NSAIDs) for treatment of rheumatoid arthritis (RA). The usefulness of these models has been validated in the clinic. The search for drugs to treat arthritis currently is focused on models for identifying drugs which may treat the chronic aspects of the disease. On September 26, 1985 the Inflammation Research Association met at the New York Academy of Sciences to discuss several murine models of chronic inflammation to access their contribution to an understanding of the human disease and their potential utility for discovery of new therapy for RA. The methylated bovine serum albumin (mBSA) model of antigen-induced monoarticular arthritis was first described in the mouse by Brackertz in 1977. Although attention has been primarily focused on the Dumonde-Glynn monoarticular arthritis rabbit model for identifying penicillamine-like drugs, the difficulty of doing extensive studies in the rabbit has led to a resurgence of interest in the mouse model, both for studying mechanisms of the arthritis and potential therapeutic agents. Dr Ian M. Hunneyball (Boots Company, Nottingham, England) presented his findings on the effects of antiarthritic drugs in the mouse model compared to the rabbit model. Drug effects were determined by examining the pathology of the knee joint, specifically the extent of synovitis and bone erosion. NSAIDs (flurbiprofen, ibuprofen and indomethacin) did not inhibit the murine arthritis. As in the rabbit arthritis, corticosteroids (prednisolone and dexamethasone) inhibited synovitis and erosion in the mouse knee joint. Moreover, sulphasalazine (but not sulphapyridine), dapsone, and immunosuppressants (azathioprine, methotrexate and cyclosporin A) inhibited both the synovitis and bony erosions. In the rabbit immunosuppresants, but not sulphasalazine, were active. While NSAID, corticosteroids and immunosuppressants have similar activities in both the rabbit and the mouse, Dr Hunneyball showed that disease-modifying antiarthritic drugs (DMARDs) had a unique profile in each of the two models: d-penicillamine and gold were therapeutic in the rabbit but without effect in the mouse model. Chloroquine was inactive in both models. Because of size and ease of handling, the mouse model would appear to be more adaptable to the discovery of novel therapeutic agents than the rabbit. Moreover, the profile of antiarthritic drugs in the mouse may indicate that this model may be best used for identifying therapeutic agents with unique mechanisms. Dr Wim B. van den Berg (University Hospital, St Radboud, Nijmegan, the Netherlands) reported his mechanistic studies in the mBSA model. He showed that BSA made cationic by methylation (mBSA) or amidation (aBSA) deeply penetrates the dense hyaline cartilage and is retained in the mouse knee joint in higher amounts and for longer periods than other antigens. Chargemediated antigen retention in the joint was demonstrated to be an important factor in the chronicity of the inflammation as shown by 99mTc uptake in the joint and by histological evaluation. Oxygen radicals and hydrogen peroxide (H202) were considered as potential mediators of the mBSA arthritis. When the respective inactivating enzymes, i.e. superoxide dismutase (SOD) and catalase were made cationic, only catalase suppressed the arthritis. Catalase was also effective in