Dose-dependent effects of alpha-naphthylisothiocyanate disconnect biliary fibrosis from hepatocellular necrosis.
Exposure of rodents to the xenobiotic α-naphthylisothiocyanate (ANIT) is an established model of experimental intrahepatic bile duct injury. Administration of ANIT to mice causes neutrophil-mediated hepatocellular necrosis. Prolonged exposure of mice to ANIT also produces bile duct hyperplasia and liver fibrosis. However, the mechanistic connection between ANIT-induced hepatocellular necrosis and bile duct hyperplasia and fibrosis is not well characterized. We examined impact of two different doses of ANIT, by feeding chow containing ANIT (0.05%, 0.1%), on the severity of various liver pathologies in a model of chronic ANIT exposure. ANIT-elicited increases in liver inflammation and hepatocellular necrosis increased with dose. Remarkably, there was no connection between increased hepatocellular necrosis and bile duct hyperplasia and peribiliary fibrosis, as these pathologies increased similarly in mice exposed to either dose of ANIT. The results indicate that the severity of hepatocellular necrosis does not dictate the extent of bile duct hyperplasia/fibrosis in ANIT-exposed mice.
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824, USA.|Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Nikita
N
Joshi
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA.
Jessica L
JL
Ray
Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA.|Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
Anna K
AK
Kopec
Department of Pharmacology & Toxicology, Michigan State University, East Lansing, MI, 48824, USA.|Department of Pathobiology & Diagnostic Investigation, Michigan State University, East Lansing, MI, 48824, USA.|Institute for Integrative Toxicology, Michigan State University, East Lansing, MI, 48824, USA.
James P
JP
Luyendyk
D015058:1-Naphthylisothiocyanate / Q000633:toxicity*; D000818:Animals; D001653:Bile Ducts, Intrahepatic / Q000378:metabolism* / Q000473:pathology; D056486:Chemical and Drug Induced Liver Injury / Q000378:metabolism* / Q000473:pathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D008105:Liver Cirrhosis, Biliary / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D009336:Necrosis
D015058:1-Naphthylisothiocyanate
ANIT; alpha-naphthylisothiocyanate; bile duct; biliary hyperplasia; fibrosis; hepatocellular necrosis; liver