The program aims to examine the significance of changes that phagocytic leukocytes undergo when they ingest bacteria, with respect to the role those changes play in protecting the host. The leukocytes may be stimulated by solid particles, or by some more soluble substances, to produce and release compounds of both leukocytic and bacterial origin. These phenomena are relevant to maintenance of health, because they provide a bulwark against infection. On the other hand, some biochemical sequelae of this stimulation may injure host cells. Generation and release of activated oxygen species is a key phenomenon in these contexts. Studies of the nature of the enzymes involved, of the """"""""trigger"""""""" mechanism for stimulation of phagocytic cells, and of morphological changes the leukocytes undergo, have been made, and will be extended. The focus will be on the effects of some to the very molecules that phagocytes release from bacteria upon the phagocytic leukocytes themselves. Some other cells may also be affected. For example, monomeric breakdown-products of bacterial cells walls are well known as immuno-adjuvants and pyrogens, and have now been found to be somnogens. Binding sites (receptors?) for these substances have been found on macrophages, and, in preliminary work, on glial but not neuronal cells. These binding sites will be characterized, their variation followed as a function of the condition of the animal, and physiological effects ascribed to the ligand related to occupancy of the cellular binding sites. Radioactive (125I) muramyl ligands have been made and the conditions for binding studies are established. Attempts to isolate the receptor (binding) proteins will employ methods that include affinity columns with immobilized peptidoglycans. Muramyl peptides (exogenous substances) and an endogenous substance (serotonin) mimic each other """"""""pharmacologically."""""""" Thus, muramyl peptides induce slow- wave sleep in which serotonin has been implicated. Indications are that the latter substance """"""""activates"""""""" macrophages, e.g., by conditioning them to release activated oxygen species upon later stimulation - a function of muramyl peptides. Work will examine aspects of the synergism between stimuli and ionophores (for Ca++) and possible physiologically significant synergistic situations. Further, environmental (bodily) components may affect the lipid matrix of the phagocytic cell - membrane, triggering release of active oxygen species as shown in vitro. Both these matters could be of importance in vivo in bacterial infections, as may be the implications of the somnogenic activity of muramyl peptides.
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