The acute‐phase response protects mice from D‐galactosamine sensitization to endotoxin and tumor necrosis factor–α

D‐Galactosamine is an hepatocyte‐specific inhibitor of RNA synthesis. It has been used to sensitize animals both to the lethal effects of bacterial endotoxin (lipopolysaccharide) and to a principal lipopolysaccharide‐induced mediator of shock, tumor necrosis factor–α. The mechanism by which this sensitization occurs is unknown. Because lipopolysaccharide, acting through a network of cytokines, provokes the transcription of a number of hepatic acute‐phase proteins, we postulated that the lipopolysaccharide‐sensitizing effect of D‐galactosamine could be caused by its inhibition of acute‐phase product transcription. We confirmed that the acute‐phase response to lipopolysaccharide was attenuated by simultaneous administration of D‐galactosamine. However, when the acute‐phase response was induced by subcutaneous turpentine 24 hr before D‐galactosamine administration, the effect of D‐galactosamine on circulating acute‐phase reactants was negligible. Furthermore, induction of an a priori acute‐phase response protected mice from both D‐galactosamine/lipopolysaccharide and D‐galactosamine/tumor necrosis factor–α‐induced death. The turpentine‐induced acute‐phase response did not decrease endogenous tumor necrosis factor–α production after lipopolysaccharide, nor did it affect the clearance of larger doses of injected tumor necrosis factor–α. Thus we suggest that the acute‐phase response protects against death in D‐galactosamine—sensitized mice through an interaction with mediators of shock subsequent to tumor necrosis factor–α release. (HEPATOLOGY 1992;15:122–129).