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Endotoxin potentiates hepatocyte apoptosis in cholestasis
Farnaz N Moazzam1, John J Brems, Sherri L Yong
1Department of Surgery, Burn & Shock Trauma Institute, Loyola University Medical Center, Maywood, IL 60153, USA.
Journal of the American College of Surgeons
|June 26, 2002
Summary
Cholestasis in rats induced apoptosis but not necrosis. A secondary endotoxin insult triggered necrosis in cholestatic livers, highlighting endotoxin
Area of Science:
- Hepatology
- Cellular Biology
- Toxicology
Background:
- Cholestasis is a common factor in liver disease, often linked to septic liver injury.
- The precise cellular mechanisms of liver injury during cholestasis and sepsis are not fully understood.
- Apoptosis, a regulated cell death pathway, was investigated as a potential mechanism.
Purpose of the Study:
- To investigate the role of apoptosis in liver injury caused by cholestasis and endotoxin.
- To determine if cholestasis predisposes the liver to necrosis upon subsequent endotoxin exposure.
Main Methods:
- Male Sprague-Dawley rats underwent bile duct ligation (cholestasis model) and/or endotoxin injection.
- Groups included bile duct-ligated+endotoxin, sham+endotoxin, bile duct-ligated, sham, endotoxin, and normal controls.
- Liver tissues were analyzed for apoptosis (TUNEL, DNA fragmentation) and necrosis, and caspase 3 activity was measured.
Main Results:
- Apoptosis was observed in livers with cholestasis, endotoxin, or both, confirmed by histological and biochemical markers.
- Necrosis (10-20%) was present in all endotoxin-treated groups.
- Caspase 3 activity was significantly elevated in endotoxin-treated rats compared to controls (p < 0.0001).
Conclusions:
- Cholestasis alone induced apoptosis in rat livers but did not progress to necrosis.
- A secondary insult of endotoxin in cholestatic livers led to apoptosis and subsequent necrosis.
- Endotoxin acts as a potent hepatotoxin, causing both apoptosis and necrosis in the liver.