Cadmium-induced acute hepatic injury is exacerbated in human interleukin-8transgenic mice

It is reported repeatedly that severe hepatocellular necrosis along with in filtration of neutrophils occurs after acute cadmium exposure. Neutrophils, which migrate by the gradient of chemoattractants such as interleukin-8, a re believed to play an important role in inflammation at the damaged sites. To investigate whether neutrophils aggravate or repair the liver injury in duced by cadmium, we checked the hepatotoxic effects of cadmium on human in terleukin-8 transgenic mice (hIL-8Tg), which overexpressed IL-8 and display ed an inability of neutrophil migration resulting from both the lack of che motactic gradient and the downregulation of L-selectin on the surface of ne utrophils. A significantly lower survival rate was observed in hIL-8Tg comp ared with wildtype mice after subcutaneous administration of cadmium. Evide nt liver injury characterized by abrupt increases in plasma GOT and GPT lev els was found in hIL-8Tg at 18 h after cadmium administration. Histological examinations, including H & E staining and esterase staining, revealed the infiltration of numerous neutrophils into the damaged liver tissues in wil d-type mice, and the inhibition of the neutrophil migration into the liver as well as enhanced hepatocellular necrosis in hIL-8Tg. Peripheral white bl ood cell and polymorphonuclear cell counts increased and reached their peak s at 12 h after cadmium administration in wild-type mice, whereas the incre ase in blood leukocyte counts was delayed in hIL-8Tg. There was no signific ant difference in the amounts of cadmium accumulated in liver and kidneys b etween wild-type mice and hIL-8Tg. In conclusion, an acute cadmium hepatoto xic effect was exacerbated in hIL-8Tg resulting from inhibited neutrophil m igration, suggesting that migrated neutrophils can prevent aggravation of l iver injury by acute cadmium administration. (C) 2000 Academic Press.