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Archives of Toxicology

, Volume 93, Issue 10, pp 2863–2878 | Cite as

Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury

  • Hu Wang
  • Rumeng Zhang
  • Yangyang Zhu
  • Tian Teng
  • Yujia Cheng
  • Apu Chowdhury
  • Jihong Lu
  • Zhanjun Jia
  • Jun Song
  • Xiaoxing YinEmail author
  • Ying SunEmail author
Molecular Toxicology

Abstract

Acetaminophen (APAP)-induced liver injury is the main cause of acute liver failure. This study investigated the role of microsomal prostaglandin E synthase 2 (mPGES-2), discovered as one of the prostaglandin E2 (PGE2) synthases, in mediating APAP-induced liver injury. Using mPGES-2 wild-type (WT) and knockout (KO) mice, marked resistance to APAP-induced liver damage was found in mPGES-2 KO, as indicated by robust improvement of liver histology, changes in liver enzyme release, and marked decrease in APAP–cysteine adducts (APAP–CYS) and inflammatory markers. Moreover, the results confirmed that increase in liver PGE2 content in KO mice under basal conditions was not critical for the protection from APAP-induced liver injury. Importantly, mPGES-2 deletion inhibited the production of malondialdehyde (MDA), increasing glutathione (GSH) level. Enhanced GSH level may contribute to the inhibition of APAP toxicity in mPGES-2 KO mice. To further elucidate the role of mPGES-2 in the liver injury induced by APAP, adeno-associated viruses (AAV) were used to overexpress mPGES-2 in the liver. The results showed that mPGES-2 overexpression aggravates liver injury associated with an increase in inflammatory markers and chemokines after APAP treatment. Moreover, a lower level of GSH was detected in the mPGES-2 overexpression group compared to the control group. Collectively, our findings indicate that mPGES-2 plays a critical role in regulating APAP-induced liver injury, possibly by regulating GSH and APAP–CYS level, which may provide a potential therapeutic strategy for the prevention and treatment of APAP-induced liver injury.

Keywords

Microsomal prostaglandin E synthase 2 Acetaminophen Liver injury Prostaglandin E2 Glutathione 

Abbreviations

APAP

Acetaminophen

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

AAV

Adeno-associated viruses

APAP–CYS

APAP–cysteine adducts

CXCL

C–X–C motif chemokine ligand

CXCR

C–X–C chemokine receptor

COX

Cyclooxygenase

dmPGE2

16,16-Dimethyl prostaglandin E2

GSH

Glutathione

IL

Interleukin

KO

Knockout

mPGES-2

Microsomal prostaglandin E synthase 2

NAPQI

N-acetylbenzoquinoneimine

PGE2

Prostaglandin E2

TNF

Tumor necrosis factor

WT

Wild type

ATP

Adenosine triphosphate

HHT

Hydroxyheptadecatrienoic acid

MDA

Malondialdehyde

HE

Hematoxylin–eosin

MCP-1

Monocyte chemoattractant protein-1

NLRP3

NLR family pyrin domain containing 3

Notes

Acknowledgements

This work was supported by the National Natural Science Foundation of China (Grant no. 81603179), the China Postdoctoral Science Foundation (Grant no. 2016M601893), the China Postdoctoral Science Special Foundation (Grant no. 2018T110555), Top-notch Academic Programs Project of Jiangsu Higher Education Institutions (PPZY2015B161) and Innovative Entrepreneurship Training Program for National College Students (Grant no. 201710313022).

Author contributions

Y Sun and XX Yin conducted the study concept and design. H Wang, RM Zhang, and YY Zhu contributed to data acquisition, data analysis, and drafting of the manuscript. T Teng, YJ Cheng, A Chowdhury, JH Lu, ZJ Jia, and J Song participated critically in the discussion and revision of the manuscript.

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflicts of interest.

Ethical standards

All procedures in this study were carried out in strict accordance with the recommendations of the Guide for the Care and Use of Laboratory Animals of China Association for Laboratory Animal Science and approved by the Animal Ethics Committee of Xuzhou Medical University.

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Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Hu Wang
    • 1
  • Rumeng Zhang
    • 1
  • Yangyang Zhu
    • 1
    • 3
  • Tian Teng
    • 1
  • Yujia Cheng
    • 1
  • Apu Chowdhury
    • 1
  • Jihong Lu
    • 1
  • Zhanjun Jia
    • 2
  • Jun Song
    • 4
  • Xiaoxing Yin
    • 1
    Email author
  • Ying Sun
    • 1
    Email author
  1. 1.Jiangsu Key Laboratory of New Drug Research and Clinical PharmacyXuzhou Medical UniversityXuzhouPeople’s Republic of China
  2. 2.Nanjing Key Laboratory of Pediatrics, Nanjing Children’s HospitalNanjing Medical UniversityNanjingPeople’s Republic of China
  3. 3.Changshu NO. 2, People’s HospitalSuzhouPeople’s Republic of China
  4. 4.Department of General SurgeryThe Affiliated Hospital of Xuzhou Medical UniversityXuzhouPeople’s Republic of China

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