Mechanisms of hepatotoxic interaction of amiodarone with inflammatory stress---A model of idiosyncratic, drug-induced liver injury
Idiosyncratic, drug-induced liver injury is a type of adverse reaction that occurs in a small fraction of patients during drug therapy. Amiodarone (AMD) is a class III antiarrythmic drug that causes idiosyncratic hepatotoxicity in human patients. The mechanisms of AMD-induced hepatotoxicity are not understood, and inflammatory stress has been proposed to be one of the contributors to idiosyncratic, drug-induced hepatotoxicity. The inflammatory stress hypothesis is supported by the work presented in this thesis demonstrating that cotreatment with AMD and the inflammagen lipopolysaccharide (LPS) results in liver damage in rats. The importance of several inflammatory factors was explored. AMD enhanced LPS-induced TNF production, coagulation system activation and fibrinolysis impairment. AMD/LPS cotreatment caused activation of neutrophils (PMNs) in the liver. Inhibition of TNF signaling, inhibition of activation of coagulation or inactivation of PMNs attenuated AMD/LPS-induced liver injury in rats, demonstrating the importance of each of these events to toxicity. The activation of PMNs in the liver after AMD/LPS cotreatment was dependent on the activation of coagulation system, suggesting interaction among these inflammatory pathways. TNF potentiated AMD-induced apoptotic cell death of Hepa1c1c7 cells, in which caspase activation and lipid peroxidation played important roles. These studies of the interaction between AMD and inflammatory responses in animals further our understanding of the mechanisms of AMD-induced idiosyncratic hepatotoxicity and provide potential targets for treatment or prevention of such reactions in human patients.
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- In Collections
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Electronic Theses & Dissertations
- Copyright Status
- In Copyright
- Material Type
-
Theses
- Authors
-
Lü, Jingtao
- Thesis Advisors
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Ganey, Patricia E.
- Committee Members
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Roth, Robert A.
LaPres, John J.
Hegg, Eric L.
DeWitt, David L.
Zacharewski, Timothy R.
- Date
- 2012
- Program of Study
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Biochemistry and Molecular Biology - Environmental Toxicology
- Degree Level
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Doctoral
- Language
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English
- Pages
- xiii, 183 pages
- ISBN
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9781267358257
1267358254
- Permalink
- https://doi.org/doi:10.25335/cmnc-7b41