Dynamic and accurate assessment of acetaminophen-induced hepatotoxicity by integrated photoacoustic imaging and mechanistic biomarkers in vivo

Nathalie Brillant, Mohamed Elmasry, Neal C Burton, Josep Monne Rodriguez, Jack W Sharkey, Stephen W Fenwick, Harish Poptani, Neil R Kitteringham, Christopher E Goldring, Anja Kipar, B. Kevin Park , Daniel J Antoine

Research output: Contribution to journalArticlepeer-review

Abstract

The prediction and understanding of acetaminophen (APAP)-induced liver injury (APAP-ILI) and the response to therapeutic interventions is complex. This is due in part to sensitivity and specificity limitations of currently used assessment techniques. Here we sought to determine the utility of integrating translational non-invasive photoacoustic imaging of liver function with mechanistic circulating biomarkers of hepatotoxicity with histological assessment to facilitate the more accurate and precise characterization of APAP-ILI and the efficacy of therapeutic intervention. Perturbation of liver function and cellular viability was assessed in C57BL/6J male mice by Indocyanine green (ICG) clearance (Multispectral Optoacoustic Tomography (MSOT)) and by measurement of mechanistic (miR-122, HMGB1) and established (ALT, bilirubin) circulating biomarkers in response to the acetaminophen and its treatment with acetylcysteine (NAC) in vivo. We utilised a 60% partial hepatectomy model as a situation of defined hepatic functional mass loss to compared acetaminophen-induced changes to. Integration of these mechanistic markers correlated with histological features of APAP hepatotoxicity in a time-dependent manner. They accurately reflected the onset and recovery from hepatotoxicity compared to traditional biomarkers and also reported the efficacy of NAC with high sensitivity. ICG clearance kinetics correlated with histological scores for acute liver damage for APAP (i.e. 3h timepoint; r=0.90, P<0.0001) and elevations in both of the mechanistic biomarkers, miR-122 (e.g. 6h timepoint; r=0.70, P=0.005) and HMGB1 (e.g. 6h timepoint; r=0.56, P=0.04). For the first time we report the utility of this non-invasive longitudinal imaging approach to provide direct visualisation of the liver function coupled with mechanistic biomarkers, in the same animal, allowing the investigation of the toxicological and pharmacological aspects of APAP-ILI and hepatic regeneration.

Original languageEnglish
Pages (from-to)64-74
Number of pages11
JournalToxicology and Applied Pharmacology
Volume332
Early online date26 Jul 2017
DOIs
Publication statusPublished - 1 Oct 2017

Keywords

  • Acetaminophen
  • Acetylcysteine
  • Alanine Transaminase
  • Animals
  • Bilirubin
  • Biomarkers
  • Cell Survival
  • Chemical and Drug Induced Liver Injury
  • Glutathione
  • HMGB1 Protein
  • Liver
  • Male
  • Mice
  • Mice, Inbred C57BL
  • MicroRNAs
  • Photoacoustic Techniques
  • Journal Article
  • Research Support, Non-U.S. Gov't

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