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Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure.

Baker LA, Lee KC, Palacios Jimenez C, Alibhai H, Chang YM, Leckie PJ, Mookerjee RP, Davies NA, Andreola F, Jalan R - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus

Levels of miR122, miR192 and miR124-1 in their respective tissues.Values are means ± SE of relative expression (2-ΔΔCt) for APAP-treated animals to both the endogenous control (miR26a) and the time-matched controls; * P < 0.05 vs. baseline at -20h.
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pone.0128076.g006: Levels of miR122, miR192 and miR124-1 in their respective tissues.Values are means ± SE of relative expression (2-ΔΔCt) for APAP-treated animals to both the endogenous control (miR26a) and the time-matched controls; * P < 0.05 vs. baseline at -20h.

Mentions: The tissue-specific miRNAs, miR122, miR192 and miR124-1, were highly expressed in their respective tissues (range: 15.7–28.4 raw Ct and -1.3–1.5 ΔCt). Levels of miR122, miR192 and miR124-1 in liver, kidney and brain tissue respectively were not significantly altered by ALF when compared to controls at the end of the study (Fig 6).


Circulating microRNAs Reveal Time Course of Organ Injury in a Porcine Model of Acetaminophen-Induced Acute Liver Failure.

Baker LA, Lee KC, Palacios Jimenez C, Alibhai H, Chang YM, Leckie PJ, Mookerjee RP, Davies NA, Andreola F, Jalan R - PLoS ONE (2015)

Levels of miR122, miR192 and miR124-1 in their respective tissues.Values are means ± SE of relative expression (2-ΔΔCt) for APAP-treated animals to both the endogenous control (miR26a) and the time-matched controls; * P < 0.05 vs. baseline at -20h.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4446266&req=5

pone.0128076.g006: Levels of miR122, miR192 and miR124-1 in their respective tissues.Values are means ± SE of relative expression (2-ΔΔCt) for APAP-treated animals to both the endogenous control (miR26a) and the time-matched controls; * P < 0.05 vs. baseline at -20h.
Mentions: The tissue-specific miRNAs, miR122, miR192 and miR124-1, were highly expressed in their respective tissues (range: 15.7–28.4 raw Ct and -1.3–1.5 ΔCt). Levels of miR122, miR192 and miR124-1 in liver, kidney and brain tissue respectively were not significantly altered by ALF when compared to controls at the end of the study (Fig 6).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Clinical Science and Services, Royal Veterinary College, Hatfield, Hertfordshire, United Kingdom.

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.

No MeSH data available.


Related in: MedlinePlus