Neutrophils generate toxic oxygen metabolities which mediate immune tissue injury. I have recently found that adenosine inhibits generation of superoxide anion (02) without interfering with lysosomal enzyme release. Adenosine, released by damaged cells and tissues, may act, therefore, as a selective """"""""endogenous antiinflammatory agent"""""""" to limit immune tissue damage mediated by toxid oxygen metabolities. Adenosine inhibits 02 generation by neutrophils exposed to soluble stimuli (such as tumor promoter phorbol myristate acetate (PMA). Since it is not known whether adenosine inhibits 02 generation stimulated by phagocytosis of immune products (aggregated IgE, BSA/anti-BSA complexes, C3b coated particles) the effects of adenosine will be determine on 02 generation stimulated by such agents. Hydrogen peroxide (H202), which participates in neutrophil mediated tissue damage, may be generated independently of 02. The effects of adenosine will be assessed on H202 generated by neutrophils exposed to soluble (C5a, FMLP, PMA) and particulate (immune complexes, C3b coated particles) agents. Since both 02 and H202 are generated as a result of the respiratory burst, the effects of adenosine will be determined on the stimulated respiratory burst of neutrophils. To and adenosine analogues will be assessed on neutrophil mediated toxicity to cultured endothelial cells and the reverse passive Arthus model of experimental arthritis. Adenosine appears to mediate its effects on neutrophils via interaction with a specific adenosine receptor on neutrophils. To further characterize the adenosine receptor on neutrophils, binding will be examined of labelled adenosine analogues to neutroplasts (nucleus and granule depleted neutrophils) and neutrophil plasma membranes isolated from neutroplasts. Since adenosine receptor stimulation is generally associated with a change in cAMP concentrations, the effects will be determined of adenosine and adenosine analgoues on cAMP concentrations in neutrophils. Interactions will be examined of adenosine with other mechanisms of signal transduction in the neutrophil. The study of the antiinflammatory properties of adenosine may lead to the development of therapeutic agents capable of specifically mitigating neutrophil mediated tissue injury in connective tissue diseases such as Rheumatoid Arthritis and Vasculitis.
