INTRODUCTION: Acetaminophen (APAP) toxicity is the number one cause of acute liver failure (ALF) and treatment options are limited. The initial toxicity is caused by the bioactivation of the drug to the reactive metabolite. However, progression of injury still occurs even after all of the drug has been eliminated from the body. APAP overdose involves sterile inflammation. Lipocalin-2 is an acute phase protein known to be upregulated in various disease models and has been observed to have a protective as well as a destructive role dependent on the model analyzed, via modulation of pro/anti-inflammatory signalling. The role of Lcn2 in a drug-induced acute liver failure model, when regeneration is inhibited, has not yet been investigated.
OBJECTIVE: This study aims to investigate the role of Lcn2 in an APAP- induced ALF model.
METHODS: An in vivo model was utilized and Lcn2KO mice were used as an intervention. Time course studies were done over a period of 0-96 hrs post APAP overdose. Liver and serum were harvested at each time point and the extent of injury was assessed via ALT/AST. Cyp2E1 and Cyp3A4 protein expression was analyzed via Western Blot. Lcn2 upregulation was analyzed via ELISA.
RESULTS: Our data demonstrated that Lcn2KO mice are protected (LD20) against APAP-induced ALF as opposed to WT (LD60). Lcn2, ALT and AST was significantly upregulated in WT mice following APAP as compared to Lcn2KO mice. CYP2E1 and CYP3A4 protein expression was comparable between WT and KO mice indicating comparable bioactivation and initial injury by APAP.
DISCUSSION: In conclusion, the protection of Lcn2KO mice from APAP overdose indicates that Lcn2 may play a role in mediating progression of injury in WT. Further studies including protein adduct formation, glutathione depletion and repletion, pro- and anti-inflammatory cytokine levels, histopathology, and proliferating cell nuclear antigen will be done to elucidate the mechanism of Lcn2 in mediating progression of injury.
Available at: http://works.bepress.com/vishakha_bhave/16/