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.
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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
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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).
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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.
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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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Wang, H., Zhang, R., Zhu, Y. et al. Microsomal prostaglandin E synthase 2 deficiency is resistant to acetaminophen-induced liver injury. Arch Toxicol 93, 2863–2878 (2019). https://doi.org/10.1007/s00204-019-02543-1
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DOI: https://doi.org/10.1007/s00204-019-02543-1