Back to Search
Start Over
Pre-treatment twice with liposomal clodronate protects against acetaminophen hepatotoxicity through a pre-conditioning effect
- Source :
- Liver Res, Liver Research, Vol 4, Iss 3, Pp 145-152 (2020)
- Publication Year :
- 2020
-
Abstract
- Background and aim Acetaminophen (APAP) overdose is a major cause of acute liver injury, but the role of macrophages in the propagation of the hepatotoxicity is controversial. Early research revealed that macrophage inhibitors protect against APAP injury. However, later work demonstrated that macrophage ablation by acute pre-treatment with liposomal clodronate (LC) exacerbates the toxicity. To our surprise, during other studies, we observed that pre-treatment twice with LC seemed to protect against APAP hepatotoxicity, in contrast to acute pre-treatment. The aim of this study was to confirm that observation and to explore the mechanisms. Methods We treated mice with empty liposomes (LE) or LC twice per week for 1 week before APAP overdose and collected blood and liver tissue at 0, 2, and 6 h post-APAP. We then measured liver injury (serum alanine aminotransferase activity, histology), APAP bioactivation (total glutathione, APAP-protein adducts), oxidative stress (oxidized glutathione (GSSG)), glutamate-cysteine ligase subunit c (Gclc) mRNA, and nuclear factor erythroid 2-related factor (Nrf2) immunofluorescence. We also confirmed the ablation of macrophages by F4/80 immunohistochemistry. Results Pre-treatment twice with LC dramatically reduced F4/80 staining, protected against liver injury, and reduced oxidative stress at 6 h post-APAP, without affecting APAP bioactivation. Importantly, Gclc mRNA was higher in the LC group at 0 h and total glutathione was higher at 2 h, indicating accelerated glutathione re-synthesis after APAP overdose due to greater basal glutamate-cysteine ligase. Oxidative stress was lower in the LC groups at both time points. Finally, total Nrf2 immunofluorescence was higher in the LC group. Conclusions We conclude that multiple pre-treatments with LC protect against APAP by accelerating glutathione re-synthesis through glutamate-cysteine ligase. Investigators using twice or possibly more LC pre-treatments to deplete macrophages, including peritoneal macrophages, should be aware of this possible confounder.
- Subjects :
- 0301 basic medicine
Drug-induced liver injury
Pharmacology
Immunofluorescence
medicine.disease_cause
Article
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Damage-associated molecular patterns (DAMPs)
medicine
Macrophage
Kupffer cells
lcsh:RC799-869
Liver injury
Hepatology
medicine.diagnostic_test
business.industry
digestive, oral, and skin physiology
Gastroenterology
Glutathione
medicine.disease
Acetaminophen
030104 developmental biology
GCLC
Acute liver failure (ALF)
Liposomal clodronate (LC)
chemistry
Toxicity
lcsh:Diseases of the digestive system. Gastroenterology
030211 gastroenterology & hepatology
Acetaminophen (APAP)
business
Oxidative stress
medicine.drug
Subjects
Details
- ISSN :
- 20962878
- Volume :
- 4
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Liver research
- Accession number :
- edsair.doi.dedup.....036e038af25964827534fdb9fbb911a7