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The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice

  • Organ Toxicity and Mechanisms
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Abstract

Acetaminophen (APAP)-induced hepatotoxicity is comprised of an injury and recovery phase. While pharmacological interventions, such as N-acetylcysteine (NAC) and 4-methylpyrazole (4-MP), prevent injury there are no therapeutics that promote recovery. JNJ-26366821 (TPOm) is a novel thrombopoietin mimetic peptide with no sequence homology to endogenous thrombopoietin (TPO). Endogenous thrombopoietin is produced by hepatocytes and the TPO receptor is present on liver sinusoidal endothelial cells in addition to megakaryocytes and platelets, and we hypothesize that TPOm activity at the TPO receptor in the liver provides a beneficial effect following liver injury. Therefore, we evaluated the extent to which TPOm, NAC or 4-MP can provide a protective and regenerative effect in the liver when administered 2 h after an APAP overdose of 300 mg/kg in fasted male C57BL/6J mice. TPOm did not affect protein adducts, oxidant stress, DNA fragmentation and hepatic necrosis up to 12 h after APAP. In contrast, TPOm treatment was beneficial at 24 h, i.e., all injury parameters were reduced by 42–48%. Importantly, TPOm enhanced proliferation by 100% as indicated by PCNA-positive hepatocytes around the area of necrosis. When TPOm treatment was delayed by 6 h, there was no effect on the injury, but a proliferative effect was still evident. In contrast, 4MP and NAC treated at 2 h after APAP significantly attenuated all injury parameters at 24 h but failed to enhance hepatocyte proliferation. Thus, TPOm arrests the progression of liver injury by 24 h after APAP and accelerates the onset of the proliferative response which is essential for liver recovery.

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Data availability

Data sharing is not applicable to this article as no datasets were generated or analyzed during the current study. All data generated or analyzed during this study are included in this published article.

Abbreviations

AIF:

Apoptosis-inducing factor

APAP:

Acetaminophen

GSH:

Glutathione

H&E:

Hematoxylin and eosin

JNK:

C-jun N-terminal kinase

MPTP:

Mitochondrial permeability transition pore

NAC:

N-Acetylcysteine

NAPQI:

N-Acetyl-p-benzoquinone imine

TPOm:

PEGylated thrombopoietin mimetic

TUNEL assay:

Terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay

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Acknowledgements

This work was funded in part by a grant from Johnson & Johnson, Consumer Health and by the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Grants R01 DK102142 and R01 DK125465, and National Institute of General Medicine (NIGMS) funded Liver Disease COBRE Grants P20 GM103549 and P30 GM118247. JYA was funded by a postdoctoral fellowship from the CTSA grant from NCATS awarded at the University of Kansas for Frontiers: University of Kansas Clinical and Translational Science Institute No. TL1TR002368.

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  1. Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, 3901 Rainbow Blvd, MS 1018, Kansas City, KS, 66160, USA

    Olamide B. Adelusi, Jephte Y. Akakpo, Anup Ramachandran & Hartmut Jaeschke

  2. Office of the Chief Medical Officer, Johnson & Johnson, Consumer Health, New Brunswick, NJ, 08901, USA

    Gary Eichenbaum & Ejaz Sadaff

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  1. Olamide B. Adelusi
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Correspondence to Hartmut Jaeschke.

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Adelusi, O.B., Akakpo, J.Y., Eichenbaum, G. et al. The thrombopoietin mimetic JNJ-26366821 reduces the late injury and accelerates the onset of liver recovery after acetaminophen-induced liver injury in mice. Arch Toxicol 98, 1843–1858 (2024). https://doi.org/10.1007/s00204-024-03725-2

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