Introduction Acute liver failure (ALF) is a life-threatening condition, and paracetamol poisoning is the major cause of ALF in the UK and US. Effective treatment relies on timely administration of N-acetylcysteine, but a significant proportion of patients will develop massive hepatocellular necrosis and progress to multi-organ failure. In these cases, therapeutic options are limited to supportive measures and liver transplantation. Further elucidation of the cellular and molecular mechanisms underpinning hepatocyte necrosis and liver repair in the context of ALF are required to allow the identification of rational, new therapeutic targets to treat patients with this devastating condition. Currently, experimental design is limited by a lack of animal models in which the injury and repair process can be imaged for more than 6–8 hours. The aim of this study was to develop an animal model of paracetamol-induced liver injury, with scope for longer-term sequential imaging than current protocols allow.
Method The mouse model of paracetamol-induced acute liver injury is well established. We have combined this model with a novel intravital imaging approach which allows sequential, real-time imaging of the liver via a surgically implanted titanium abdominal imaging window (AIW). This technique, in conjunction with multiphoton microscopy and other label-free imaging modalities, allows us to image the processes involved in acute liver injury and repair at cellular and subcellular resolution sequentially and in real-time.
Results Here we show that the liver can be imaged sequentially over many days in the same live mouse in both normal homeostasis and following acute liver injury. We will present data where we have used a range of transgenic fluorescent reporter mice which allow cell-specific imaging of multiple hepatic lineages, in conjunction with multiphoton microscopy, coherent anti-stokes Raman scattering (CARS) microscopy and second harmonic generation, to build up a rich dataset examining the various cellular, subcellular, vascular and extracellular matrix processes and interactions involved during acute liver injury and repair.
Conclusion We hope that by further developing and utilising this new intravital imaging approach we will uncover novel insights into the biological processes governing liver injury and repair, which will in turn generate rational therapeutic targets to treat patients with acute liver failure.
Disclosure of Interest None Declared
- acute liver injury
- intravital imaging
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