. The monocyte/macrophage derived cytokine, tumor necrosis factor/cachectin (TNF) is recognized as an important contributing factor to a variety of disease states, and in particular to the lethal effects of septic or endotoxic shock. Despite intensive efforts at therapeutic intervention, mortality arising from endotoxin shock remains high at between 25-40 percent. Reports published previously by the investigator demonstrated that pretreatment of mice with hydrazine sulfate (HS) provided significant protection against the lethal effects of endotoxin. Protection was comparable to that obtained with a TNF. Recently, it has been established that the same hydrazine sulfate pretreatment also protects mice (sensitized by D-galactosamine treatment) from direct TNF lethality. The experiments outlined in this new proposal will define the biochemical and cellular mechanisms responsible for the HS mediated protection against endotoxin and TNF.
Four Specific Aims are described: The first will focus on potential effects of hydrazine sulfate on the macrophage-monocyte. This cell type has been implicated as a major target of endotoxin in mediating the production of TNF, and specific experiments are designed to assess whether HS (in vitro or in vivo) negatively affects the capacity of these cells to produce TNF in response to endotoxin or other stimuli. Second, it will be determined whether HS has effects on potential target cells which might respond to TNF. Related to this aim is the recent report that HS treated fibroblasts are less susceptible to TNF mediated cytolysis. Third, the possibility that protection against endotoxin, mediated by HS, may involve factors other than the TNF/macrophage axis will be examined. The particular focus in these studies will be the regulation of hormonal effects at the level of the adrenal/pituitary. Finally, experiments are proposed to assess the potential efficacy of HS in other experimental models of infectious disease in which TNF has been implicated. Successful completion of these proposed studies is expected to provide valuable information on both the cellular and biochemical mechanisms involved in HS mediated protection of mice against endotoxin and/or TNF lethality and the potential use of HS as a therapeutically valuable agent in human disease.
