Abstract
Overdose with acetaminophen (APAP) results in acute liver failure in humans and experimental animals. Complement comprises more than 30 proteins that can participate in tissue injury and/or repair, but the role of complement activation in APAP-induced hepatotoxicity has not been evaluated. Treatment of male, C57BL6J mice with APAP (200–400 mg/kg) resulted in liver injury as evidenced by increased activity of alanine aminotransferase (ALT) in plasma and hepatocellular necrosis. Plasma concentration of the complement component C3 was significantly reduced 6 h after treatment with APAP, indicating complement activation, and C3b (detected by immunostaining) accumulated in the centrilobular areas of liver lobules. Pretreatment with cobra venom factor (CVF; 15 U/mouse) to deplete complement components abolished APAP-mediated C3b accumulation, and this was accompanied by reductions in plasma ALT activity, hepatocellular necrosis, hepatic neutrophil accumulation, and expression of inflammatory genes (interleukin-6, interleukin-10, and plasminogen activation inhibitor-1) at 24 h after APAP treatment. Loss of hepatocellular GSH was similar in APAP-treated mice pretreated with either saline or CVF, suggesting that CVF pretreatment did not affect APAP bioactivation. Mice with a genetic deficiency in C3 had reduced ALT activity 6 and 12 h after APAP administration compared with wild-type animals. These results reveal a key role for complement activation in hepatic inflammation and progression of injury during the pathogenesis of APAP-induced hepatotoxicity.
Footnotes
This research was supported by the National Institutes of Health National Institute of Diabetes and Digestive and Kidney Diseases [Grant R01-DK087886].
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS:
- APAP
- acetaminophen
- ALT
- alanine aminotransferase
- BrdU
- 5′-bromo-2′-deoxyuridine
- CVF
- cobra venom factor
- C3
- complement component 3
- GAPDH
- glyceraldehyde-3-phosphate dehydrogenase
- IL
- interleukin
- NAPQI
- N-acetyl-p-benzoquinoneimine
- PAI-1
- plasminogen activation inhibitor-1
- PBS
- phosphate-buffered saline
- PCNA
- proliferating cell nuclear antigen
- PCR
- polymerase chain reaction
- PMN
- polymorphonuclear neutrophil
- Sal
- saline
- TNF-α
- tumor necrosis factor-α.
- Received November 8, 2011.
- Accepted February 6, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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