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Generation of a Rat Model of Acute Liver Failure by Combining 70% Partial Hepatectomy and Acetaminophen
Published on: November 27, 2019
Complement activation in acetaminophen-induced liver injury in mice
Rohit Singhal1, Patricia E Ganey, Robert A Roth
1Department of Pharmacology and Toxicology, and Center for Integrative Toxicology, Michigan State University, East Lansing, Michigan, USA.
The Journal of Pharmacology and Experimental Therapeutics
|February 10, 2012
Summary
Complement activation plays a crucial role in acetaminophen (APAP) overdose-induced liver injury. Depleting complement components reduces liver damage and inflammation, highlighting its therapeutic potential in APAP hepatotoxicity.
Area of Science:
- Immunology
- Hepatology
- Toxicology
Background:
- Acetaminophen (APAP) overdose is a leading cause of acute liver failure.
- The role of the complement system in APAP-induced liver injury remains largely uninvestigated.
- Complement proteins are involved in both tissue damage and repair processes.
Purpose of the Study:
- To evaluate the role of complement activation in the pathogenesis of APAP-induced hepatotoxicity.
- To investigate the effects of complement depletion on APAP-induced liver injury markers.
Main Methods:
- Male C57BL6J mice were treated with APAP (200-400 mg/kg) to induce liver injury.
- Complement activation was assessed by measuring plasma C3 levels and C3b deposition in liver tissue.
- Mice were pretreated with cobra venom factor (CVF) to deplete complement components or were genetically deficient in C3.
- Liver injury was evaluated by measuring plasma alanine aminotransferase (ALT) activity, hepatocellular necrosis, neutrophil infiltration, and inflammatory gene expression.
Main Results:
- APAP treatment led to significant liver injury, characterized by elevated ALT and hepatocellular necrosis.
- Reduced plasma C3 and increased C3b deposition in centrilobular areas indicated complement activation post-APAP.
- CVF-mediated complement depletion significantly reduced APAP-induced ALT activity, necrosis, neutrophil accumulation, and inflammatory gene expression.
- Hepatocellular glutathione levels were unaffected by CVF pretreatment, suggesting APAP bioactivation was not altered.
- Mice deficient in C3 exhibited reduced ALT activity following APAP administration.
Conclusions:
- Complement activation is a key contributor to liver inflammation and injury progression in APAP overdose.
- Complement depletion ameliorates APAP-induced hepatotoxicity, suggesting complement inhibition as a potential therapeutic strategy.
- These findings elucidate a novel mechanism in APAP hepatotoxicity, implicating the complement system in its pathogenesis.
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