STUDIES ON THE PATHOGENESIS OF FEVER

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Abstract
The production of endogenous pyrogen by intact granulocytes obtained from acute peritoneal exudates is blocked by arsenite, iodoacetate, p-chloromercuribenzoate, and N-ethylmaleimide in concentration of 2 x 10 -4M. When the concentration of these surfhydryl-reactive enzyme inhibitors is increased to 2 x 10-2M, only the iodoacetate inactivates the pyrogen molecule, whereas the arsenite, the p-chloromercuribenzoate, and the N-ethylmaleimide have no gross effect upon its thermogenic activity. Both diisopropyl fluorophosphate and dinitrofluorobenzene are even more potent inactivators of the pyrogen molecule than iodoacetate, although the action of the DFP cannot be blocked or reversed by known antagonists such as 2-pyridine aldoxime methiodide and hydroxylamine. Proteolytic enzymes, potentially capable of degrading leucocytic pyrogen, are released from polymorphonuclear leukocytes, along with the pyrogen, when the cells are incubated in normal salt solution. These enzymes are readily activated by a sufficient concentration of glutathione (2 x 10-2[image]). They are not present in preparations of partially purified leukocytic pyrogen from which much of the non-pyrogenic protein has been removed. Glutathioneby itself, even at concentrations as high as 2 x 10-1[image], does not grossly affect the thermogenic activity of the purified pyrogen. The implications of these findings in relation to both the production and the chemical characteristics of leukocytic pyrogen are discussed.