Acute ANIT Toxicity in Male IL-10 Knockout and Wild-type Mice

Abstract

The innate immune response is known to modify hepatocellular injury induced by toxicants. To assess the role of IL-10, a component of the innate immune response, in toxicant-induced injury of biliary epithelium, wild-type (WT) and IL-10 knockout mice (KO) were given a single toxic dose (50 mg/kg) of a-napthylisothiocyanate (ANIT) and assessed at twenty-four-hour intervals for four days following treatment. Clinical signs of toxicity were greater in WT mice. Unexpectedly, over the course of the study, there was a consistent tendency for ANIT-treated IL-10 KO mice to have less hepatocellular injury than WT mice. However, changes in the biliary epithelium differed in that there was more histologic evidence of inflammation and necrosis on days 2 and 3, respectively, in ANIT-treated IL-10 KO mice compared with WT mice. Proliferation of biliary epithelium and hepatocytes was greater and/or occurred earlier in the ANIT-treated IL-10 KO mice compared with the ANIT-treated WT mice, suggesting a greater reparative response was needed for recovery after toxicant injury in the IL-10 KO mice. Overall, our data suggest that IL-10 KO mice have less hepatocellular injury than WT mice following a toxic dose of ANIT and that biliary epithelial injury is accentuated in the KO mice.

Yinzhihuang attenuates ANIT-induced intrahepatic cholestasis in rats through upregulation of Mrp2 and Bsep expressions

“…ANIT-induced cholestasis is characterized by elevation of serum transaminases and bile acids, necrosis of hepatobiliary cells, and infiltration of inflammatory cells, followed by obstruction and proliferation of bile ducts (17,18). ANIT selectively damages bile-duct epithelial cells and causes cholangitis and subsequent intrahepatic cholestasis (24).…”

“…ANITinduced cholestasis is characterized by elevation of serum transaminases and bile acids, necrosis of hepatobiliary cells, and infiltration of inflammatory cells, followed by obstruction and proliferation of bile ducts (15)(16)(17)(18). The biomarkers for liver injury and cholestasis peak at 48 h after ANIT treatment and recover a week later.…”

Role of the lipid-regulated NF-κB/IL-6/STAT3 axis in alpha-naphthyl isothiocyanate-induced liver injury

“…Furthermore, ANIT induces damage of the bile duct epithelium leading to cholestasis. Inflammatory factors were also found to play a key role in ANIT-induced hepatotoxicity (Faiola et al 2010; Kodali et al 2006). …”

Lipidomics reveal aryl hydrocarbon receptor (Ahr)-regulated lipid metabolic pathway in alpha-naphthyl isothiocyanate (ANIT)-induced intrahepatic cholestasis

“…Drug toxicity mechanism can be well understood through deeply elucidating ANIT-induced liver toxicity in rodents. Multifaceted mechanisms have been indicated to contribute ANIT-induced liver damage, including metabolic factors and inflammation factors (Dietrich et al, 2001; Faiola et al, 2010; Kodali et al, 2006).…”