Fundamental differences during Gram-positive versus Gram-negative sepsis become apparent during bacterial challenge of D-galactosamine-treated mice

Abstract

Gram-negative and Gram-positive bacteria have been compared with respect to lethal effects when each is administered to normal and D-galactosamine-sensitized mice, both with and without concomitant dexamethasone treatment. In the case of Escherichia coli, the extent of sensitization by D-galactosamine treatment (10,000-fold) and the relative magnitude of the corresponding protection with dexamethasone (150-fold) are both consistent with an expected significant role of LPS in production of TNFα that then mediates lethal toxicity. With Staphylococcus aureus, however, marginal sensitization by D-galactosamine (5-fold) and a corresponding lack of dexamethasone protection indicate a reduced role for TNFα as a lethal mediator. In vitro comparisons of TNFα release from E. coli and S. aureus stimulated peritoneal macrophages (100-fold difference) add further support to this conclusion. Endotoxin hypo-responsive mice (C3H/HeJ) infected with E. coli are not protected by dexamethasone. Each of these comparisons indicate that the contribution of TNFα to the pathophysiological manifestations of experimental sepsis may vary substantially even among extracellular bacteria and, correspondingly, that differential dexamethasone protection may serve a discriminatory function for the potential involvement of this cytokine.