The Role of Lipocalin‐2 (Lcn2) in Acetaminophen Induced Acute Liver Failure

Acetaminophen (APAP) toxicity is the number one cause of acute liver failure, and treatment options are limited. The initial toxicity is caused by the bio‐activation of the drug to the reactive metabolite, N‐acetyl‐p‐benzoquinone imine (NAPQI). 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 innate immune protein that is known to be up‐regulated in various disease models and has been observed to have a protective as well as destructive role dependent on the model analyzed. Studies have shown that Lcn2 acts as an anti‐inflammatory modulator in low doses of toxicity, when pro‐mitogenic signaling is activated. In contrast, these repair and regeneration pathways are shown to be inhibited in a high dose model of toxicity, which ultimately leads to acute liver failure. The role of Lcn2 in a high dose model of toxicity has not yet been investigated. This study aims to investigate the role of Lcn2 in drug induced acute liver failure (APAP overdose) model and the mechanism of its involvement. An in vivo model of acute liver failure will be utilized and Lcn2 −/− mice will be used as our intervention. We hypothesize that Lcn2 −/− mice will be protected from APAP induced acute liver failure. Time course studies will be done over a period of 0–96 hours post APAP overdose. Liver and serum will be harvested at each time point and extent of injury will be assessed via ALT/AST assays and H&E staining. Bio‐activation studies will be done to determine any differences in the metabolism of the drug between the treatment groups, which include protein adduct formation and glutathione depletion and replenishment. Pro‐ and anti‐inflammatory cytokines will be measured to elucidate the role of Lcn2 in mediating progression of injury. Proliferating cell nuclear antigen (Pcna) staining will be done as a marker of liver regeneration. Our preliminary data demonstrate 20% lethality in Lcn2 −/− mice and 60% lethality in WT mice subjected to APAP overdose. In conclusion, the protection of Lcn2 −/− mice from APAP overdose indicates that Lcn2 may play a role in mediating progression of injury. Further experiments will be done to elucidate the mechanism of action. Support or Funding Information Philadelphia College of Osteopathic Medicine‐Division of Research