THE TEMPORAL RELATIONSHIP BETWEEN BACTERIAL LIPOPOLYSACCHARIDE AND MONOCROTALINE EXPOSURES INFLUENCES TOXICITY: SHIFT IN RESPONSE FROM HEPATOTOXICITY TO NITRIC OXIDE-DEPENDENT LETHALITY

Abstract

Liver injury from a variety of hepatotoxicants, including the food-borne phytotoxin monocrotaline (MCT), can be augmented by exposure to a noninjurious dose of the inflammagen bacterial lipopolysaccharide (LPS). In a previous study, a nontoxic dose of LPS given 4 h after MCT resulted in synergistic hepatotoxicity within 12-18 h. This study was designed to determine whether temporal differences in MCT and LPS exposure affect toxicity. When LPS (3.4 2 10 6 EU/kg; iv) was given one hour before MCT (100 mg/kg; ip), hepatotoxicity developed between 4 and 8 h after MCT administration, and mortality was much greater than when LPS was administered 4 h after MCT. To explore this difference, the temporal relationship between LPS and MCT exposure (7.4 2 10 6 EU/kg and 100 mg/kg, respectively) was altered. Twenty-four-hour survival was high in animals that received LPS 4 h before (86%) or after (88%) MCT, but it decreased markedly when LPS was administered 1 h before MCT (17%). Using this latter dosing regimen, animals became moribund as early as 4 h after MCT administration. Since liver injury was similar from regimens that differed greatly in mortality, death appeared to result from extrahepatic causes. To explore a role for nitric oxide (NO)-induced shock in this regimen, animals were treated with aminoguanidine (AG), an inhibitor of inducible NO synthase, prior to administration of LPS given an hour before MCT. In the cotreated animals, AG significantly attenuated mortality and decreased plasma nitrate/nitrite concentrations, markers of NO biosynthesis. Hence, the primary target of toxicity from MCT and LPS cotreatment appeared to shift from the liver to an extrahepatic site or sites as exposure to these agents occurred closer together temporally. NO appears to be causally involved in the deaths of animals treated with LPS 1 h before MCT.