title: Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure.
abstract: Acute liver failure is a rare but catastrophic condition which can progress rapidly to multi-organ failure. Studies investigating the onset of individual organ injury such as the liver, kidneys and brain during the evolution of acute liver failure, are lacking. MicroRNAs are short, non-coding strands of RNA that are released into the circulation following tissue injury. In this study, we have characterised the release of both global microRNA and specific microRNA species into the plasma using a porcine model of acetaminophen-induced acute liver failure. Pigs were induced to acute liver failure with oral acetaminophen over 19h±2h and death occurred 13h±3h thereafter. Global microRNA concentrations increased 4h prior to acute liver failure in plasma (P<0.0001) but not in isolated exosomes, and were associated with increasing plasma levels of the damage-associated molecular pattern molecule, genomic DNA (P<0.0001). MiR122 increased around the time of onset of acute liver failure (P<0.0001) and was associated with increasing international normalised ratio (P<0.0001). MiR192 increased 8h after acute liver failure (P<0.0001) and was associated with increasing creatinine (P<0.0001). The increase in miR124-1 occurred concurrent with the pre-terminal increase in intracranial pressure (P<0.0001) and was associated with decreasing cerebral perfusion pressure (P<0.002). Conclusions: MicroRNAs were released passively into the circulation in response to acetaminophen-induced cellular damage. A significant increase in global microRNA was detectable prior to significant increases in miR122, miR192 and miR124-1, which were associated with clinical evidence of liver, kidney and brain injury respectively.
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Luisa A
authors.initials: LA
authors.lastname: Baker
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Karla C L
authors.initials: KC
authors.lastname: Lee
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Carolina
authors.initials: C
authors.lastname: Palacios Jimenez
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Hatim
authors.initials: H
authors.lastname: Alibhai
authors.affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.
authors.forename: Yu-Mei
authors.initials: YM
authors.lastname: Chang
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Leckie
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Rajeshwar P
authors.initials: RP
authors.lastname: Mookerjee
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Nathan A
authors.initials: NA
authors.lastname: Davies
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Fausto
authors.initials: F
authors.lastname: Andreola
authors.affiliation: Liver Failure Group, University College London Institute for Liver and Digestive Health, University College London Medical School, Royal Free Hospital, London, United Kingdom.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Jalan
mesh_terms: D000082:Acetaminophen / Q000009:adverse effects*; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000097:blood*; D004195:Disease Models, Animal; D007427:Intracranial Pressure / Q000187:drug effects; D017114:Liver Failure, Acute / Q000097:blood* / Q000139:chemically induced*; D035683:MicroRNAs / Q000097:blood*; D013552:Swine
chemical_list: D035683:MicroRNAs; D000082:Acetaminophen