It is estimated that almost twenty-five to thirty-five million Americans consisting of persons of all ages and sex suffer from one or the other form of a degenerative connective tissue disease. These diseases involve complex biochemical changes and, although great progress has been made in our understanding of these changes, the picture is far from complete. In this regard, our long term objective is to fully understand the role(s) of endogenous copper (Cu) and Cu-containing enzymes (e.g. Cu, Zn-Superoxide dismutase, ceruloplasmin (Cp), etc.) in both acute and chronic inflammation. As a follow-up to our current studies, the major specific aims of the present proposal are to 1) carry out mechanistic studies to determine the biochemical/cellular basis of increased carrageenin paw edema (CE) in nutritionally Cu-def. rats; 2) to further investigate the immunosuppressive effects of nutritional Cu-def. on antibody production against Type III pneumococcal polysaccharide (S3) in the rat; and 3) to examine the effects of nutritional Cu-def. on reverse passive Arthus reaction (RPAR) and collagen-induced arthritis (CIA) in the rat. In order to investigate the biochemical/cellular basis of increased CE in Cu-def. rats a series of experiments will be conducted to seek answers to questions such as: do neutrophils from Cu-def. rats generate more superoxide or arachadonic acid metabolites; do Cu-def. rats show increased vascular permeability; are the effects of Cu-def. reversible upon Cu supplementation or upon treatment with Cu, Zn-SOD, Cp, non- steroidal antiinflammatory drugs; do Cu-def. rats still show greater inflammation when the latter is induced by specific mediators, etc. Effects of Cu-def. on antibody production against S3 will be investigated by measuring IgM anti-S3 production after 20, 40, 60 days feeding of a Cu-def. diet and the specificity of the effects will be checked by studying reversibility following Cu supplementation. The effects of Cu- def. on RPAR and CLA will be studied following 60 days feeding of a Cu-def diet. In RPAR, effects of pretreatment with novel antiinflammatory drugs chloroquine and levamisole will be studied. In CLA, the effects will be quantified by measuring the serum concentrations of IgM rat anti-collagen and IgG rat anti- collagen antibodies. In all experiments, Cu-def. or Cu- supplementation will be confirmed by measuring the concentration of Cu and activities of Cu,Zn-SOD, and cp in relevant tissues.
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