Hemolysis has been shown to be important in the depression of Kupffer cell function and host defense after thermal injury. Phagocytosis of erythrocytes depresses macrophage function. Our recent studies have shown that the phagocytosis of erythrocyte ghosts does not depress host defense suggesting that erythrocyte contents are important in depressing Kupffer cell function. It was also shown that the recovery of macrophage function was associated with digestion of the phagocytized erythrocytes. The hypothesis of the proposed project is that scavengers of reactive oxygen metabolites within erythrocytes that have been phagocytized depress macrophage bactericidal function.
The specific aims of the project are: 1) to determine the effect of erythrocyte-contained scavengers of reactive oxygen metabolites on macrophage immune receptor and bactericidal function. This will be approached by studying the in vivo and in vitro effect of the phagocytosis of erythrocytes in which certain scavengers have been inactivated and the effect of the ingestion of specific scavengers contained within liposomes. 2) To determine if the phagocytosis of erythrocytes depresses the in vitro respiratory burst response to soluble and phagocytic stimuli in macrophages. The effect of the prior ingestion of scavengers of reactive oxygen metabolites contained within erythrocytes or liposomes on the expression of the products of the respiratory burst will be determined. 3) To determine the effect of macrophage activation on the rate of recovery of macrophage function following erythrocyte phagocytosis. Lysosomal enzyme activity in macrophages will be related to the rate of digestion of phagocytized erythrocytes. The recovery of normal macrophage bactericidal function should not be possible when scavengers of reactive oxygen metabolites are present within the macrophage. Electron microscopy will be used to evaluate the rate of digestion of phagocytized erythrocytes. The long-range objective of this project is to elucidate the mechanism of the depression of host defense function in severely injured patients and thereby to provide a basis for improved diagnosis and treatment of these patients.
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