title: Cadmium-induced acute hepatic injury is exacerbated in human interleukin-8 transgenic mice.
abstract: It is reported repeatedly that severe hepatocellular necrosis along with infiltration of neutrophils occurs after acute cadmium exposure. Neutrophils, which migrate by the gradient of chemoattractants such as interleukin-8, are believed to play an important role in inflammation at the damaged sites. To investigate whether neutrophils aggravate or repair the liver injury induced by cadmium, we checked the hepatotoxic effects of cadmium on human interleukin-8 transgenic mice (hIL-8Tg), which overexpressed IL-8 and displayed an inability of neutrophil migration resulting from both the lack of chemotactic gradient and the downregulation of l-selectin on the surface of neutrophils. A significantly lower survival rate was observed in hIL-8Tg compared with wild-type mice after subcutaneous administration of cadmium. Evident liver injury characterized by abrupt increases in plasma GOT and GPT levels 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 wild-type mice, and the inhibition of the neutrophil migration into the liver as well as enhanced hepatocellular necrosis in hIL-8Tg. Peripheral white blood cell and polymorphonuclear cell counts increased and reached their peaks at 12 h after cadmium administration in wild-type mice, whereas the increase in blood leukocyte counts was delayed in hIL-8Tg. There was no significant difference in the amounts of cadmium accumulated in liver and kidneys between wild-type mice and hIL-8Tg. In conclusion, an acute cadmium hepatotoxic effect was exacerbated in hIL-8Tg resulting from inhibited neutrophil migration, suggesting that migrated neutrophils can prevent aggravation of liver injury by acute cadmium administration.
authors.affiliation: Department of Public Health, Faculty of Medicine, Fukushima Medical University, 1 Hikarigaoka, Fukishima, 960-1295, Japan. hhyogo@jichi.ac.jp
authors.forename: H
authors.initials: H
authors.lastname: Horiguchi
authors.forename: A
authors.initials: A
authors.lastname: Harada
authors.forename: E
authors.initials: E
authors.lastname: Oguma
authors.forename: M
authors.initials: M
authors.lastname: Sato
authors.forename: Y
authors.initials: Y
authors.lastname: Homma
authors.forename: F
authors.initials: F
authors.lastname: Kayama
authors.forename: M
authors.initials: M
authors.lastname: Fukushima
authors.forename: K
authors.initials: K
authors.lastname: Matsushima
mesh_terms: D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D001219:Aspartate Aminotransferases / Q000097:blood; D002104:Cadmium / Q000493:pharmacokinetics; D002105:Cadmium Poisoning / Q000401:mortality / Q000473:pathology*; D056486:Chemical and Drug Induced Liver Injury / Q000401:mortality / Q000473:pathology*; D006801:Humans; D016209:Interleukin-8 / Q000096:biosynthesis / Q000502:physiology*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D007958:Leukocyte Count / Q000187:drug effects; D008099:Liver / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000097:blood; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D020556:Neutrophil Infiltration / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019087:Selectins / Q000096:biosynthesis; D016019:Survival Analysis
chemical_list: D016209:Interleukin-8; D019087:Selectins; D002104:Cadmium; D008668:Metallothionein; D001219:Aspartate Aminotransferases; D000410:Alanine Transaminase