FUNDAMENTAL DIFFERENCES DURING GRAM-POSITIVE VERSUS GRAM-NEGATIVE SEPSIS BECOME APPARENT DURING BACTERIAL CHALLENGE OF D-GALACTOSAMINE-TREATED MICE

Gram-negative and Gram-positive bacteria have been compared with respe ct to lethal effects when each is administered to normal and D-galacto samine-sensitized mice, both with and without concomitant dexamethason e treatment. In the case of Escherichia coli, the extent of sensitizat ion by D-galactosamine treatment (10,000-fold) and the relative magnit ude of the corresponding protection with dexamethasone (150-fold) are both consistent with an expected significant role of LPS in production of TNF alpha that then mediates lethal toxicity. With Staphylococcus aureus, however, marginal sensitization by D-galactosamine (5-fold) an d a corresponding lack of dexamethasone protection indicate a reduced role for TNF alpha as a lethal mediator. In vitro comparisons of TNF a lpha release from E. coli and S. aureus stimulated peritoneal macropha ges (100-fold difference) add further support to this conclusion. Endo toxin hyporesponsive mice (C3H/HeJ) infected with E. coli are not prot ected by dexamethasone. Each of these comparisons indicate that the co ntribution of TNF alpha to the pathophysiological manifestations of ex perimental sepsis may vary substantially even among extracellular bact eria and, correspondingly, that differential dexamethasone protection may serve a discriminatory function for the potential involvement of t his cytokine.