Research Projects

Increased inflammation, hepatocyte damage, and neutrophil infiltration manifest the pathogenesis of drug-induced liver injury (DILI) and progression of non-alcoholic fatty liver disease (NAFLD) to non-alcoholic steatohepatitis (NASH). DILI further culminates into acute liver failure. Previous studies in patients have demonstrated that NAFLD/NASH patients develop accelerated and exacerbated liver damage to drug-induced insults as compared to controls. Prior studies in animal models show that mice fed on high fat and acetaminophen have increased transaminase levels as compared to lean mice. Furthermore, depleting neutrophils in murine models of acetaminophen-induced liver injury (AILI) attenuates liver damage. However, the significance of neutrophils or therapeutic targeting of neutrophils is yet to be explored in the combined liver injury model of NAFLD and AILI. Neutrophils are shown to help in resolving inflammation at the later stages of liver disease, therefore, we further hypothesize that different phenotypes of neutrophil at different stages contribute to liver injury in this combined liver injury model. Neutrophils release neutrophil extracellular traps, which can induce fibrosis; however, the role of NETs in promoting hepatocyte repair, damage, or death is not known. We further postulate that the NETome of this combined liver injury model is composed of unique damage-associated molecule patterns that accelerate liver damage. Extracellular vesicles (EVs) are small bi-membrane vesicles that are involved in inter-cellular and inter-organ communication. Prior studies demonstrated an increase in EV number in circulation in DILI, however, the role of neutrophil-derived EVs is not yet explored. We hypothesize that neutrophil-derived EVs may play an important role in regulating hepatocyte damage and inflammation in the liver. This project will determine the role of neutrophils in DILI associated with NAFLD/NASH. In objective 1, we will characterize neutrophil infiltration, phenotype, and activation in vitro and in vivo. Objective 2 will investigate the role of NETs in relation to hepatocyte damage and the composition of NETs referred to as “NETome.” Lastly, in objective 3, we will assess the function of neutrophil-derived exosome cargo. The successful completion of this project will identify the multifaceted role of neutrophils in accelerated liver damage in the DILI associated with NAFLD/NASH.