Enhanced Xenobiotic-Induced Hepatotoxicity and Kupffer Cell Activation by Restraint-Induced Stress

Abstract

We tested the hypothesis that environmental stress is a predisposing factor for liver injury by examining the effect of acute restraint on liver injury provoked by carbon tetrachloride (CCl4) and allyl alcohol. Mice were immobilized using Plexiglas restraint cages, producing a form of psychogenic stress, whereas other animals were allowed to roam free. Serum alanine aminotransferase levels were elevated significantly in restrained animals after administration of varying doses of CCl4 or allyl alcohol that did not produce liver injury in unrestrained animals. This enhanced liver injury after CCl4 was seen in both male and female mice. The duration of acute restraint was found to be important because a period of 2.5 h of restraint enhanced hepatotoxicity, whereas shorter periods of restraint did not significantly increase liver injury. Serum corticosterone concentrations increased, whereas hepatic glutathione content decreased during and after acute restraint. In addition, delay in administration of CCl4 until 5 h after completion of restraint also produced an elevated level of liver injury compared with that seen in free roaming animals. Immunohistochemical examination of the livers showed significantly enhanced Kupffer cell activation in restrained mice compared with that of free roaming mice. These observations suggest that induction of psychogenic stress may increase the susceptibility to liver injury observed with classic hepatotoxicants and may represent an important predisposing factor to liver injury after xenobiotic exposure. The underlying mechanism seems to be increased macrophage activation in the liver, which may subsequently sensitize hepatocytes to xenobiotics and thus enhance hepatotoxicity.