Investigation of possible mechanisms of hepatic swelling and necrosis caused by acetaminophen in mice.

Vascular congestion and liver swelling have long been recognized as features of the hepatotoxic effects of acetaminophen (AAP) in mice and rats and have been proposed as contributing factors to the eventual extent of necrosis produced. Neutrophil accumulation in the hepatic microcirculation has been proposed as being responsible for the blockage of hepatic blood flow and thereby the expansion of the region of damage. We therefore determined in mice the effects of hepatotoxic doses of AAP on the messenger RNA for intercellular adhesion molecule-1 (ICAM-1), which is a critical determinant of neutrophil adhesion, activation and ultimately of neutrophil-mediated tissue injury. Hepatotoxic doses of AAP did not upregulate ICAM-1 messenger RNA. However, doses of bacterial lipopolysaccharide (LPS) did cause a rapid and dramatic increase in ICAM-1 message, which was accompanied by a much greater hepatic accumulation of neutrophils, but which led to only scattered single cell necrosis. In addition, we investigated the effects of pentoxifylline (PTX) on AAP-induced vascular congestion and on hepatic necrosis as evaluated histologically and by measurement of plasma transaminase activities. Although PTX has been shown to increase blood cell deformability and improve vascular perfusion in a number of animal models of restricted blood flow, and is used in humans for the treatment of intermittent claudication, we found no decrease in AAP-induced hepatic swelling or in AAP-induced necrosis in response to PTX. With some dosing regimens, PTX-treated animals proved to be slightly more susceptible to AAP, which may be related to the reported potentiation of the cytotoxicities of a number of alkylating anti-cancer drugs by PTX and other methylxanthines. We conclude from these studies that upregulation of ICAM-1 and subsequent adhesion and vascular plugging by neutrophils are not significant determinants of AAP-induced liver swelling and necrosis and that whatever hemorheological advantages PTX might offer in AAP-induced hepatic damage appear to be overshadowed by effects that potentiate the toxic responses.