Item – Theses Canada

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OCLC number
55596661
Link(s) to full text
LAC copy
LAC copy
Author
Card, Jeffrey William,1973-
Title
Mechanistic studies of amiodarone-induced pulmonary toxicity.
Degree
Ph. D. -- Queen's University, 2002
Publisher
Ottawa : National Library of Canada = Bibliothèque nationale du Canada, [2003]
Description
3 microfiches.
Notes
Includes bibliographical references.
Abstract
Amiodarone (AM) is an efficacious antidysrhythmic agent that is associated with numerous adverse effects, including potentially life-threatening pulmonary fibrosis. The current research investigated mitochondrial dysfunction as a potential initiating mechanism of AM-induced pulmonary toxicity (AIPT), and assessed the ability of vitamin E and pirfenidone to alleviate AIPT in a hamster model. 'In vitro' exposure of isolated hamster lung mitochondria to AM or its primary metabolite, N-desethylamiodarone (DEA), resulted in significant drug accumulation coinciding with inhibition of respiratory function and collapse of inner mitochondrial membrane potential. The effects of DEA were more pronounced and/or more rapid in onset than those of AM, and induction of lipid peroxidation was not associated with the mitochondrial effects of either drug. Intratracheal administration of AM to hamsters resulted in inhibition of lung mitochondrial respiratory function as early as 1 hour post-dosing, that persisted for up to 24 hours, while indicators of lung cell injury (lactate dehydrogenase (LDH) activity and total protein content in bronchoalveolar lavage fluid) were elevated early after AM dosing. Thus, mitochondrial dysfunction may play a role in initiating lung cell damage that leads to the fibrotic response to AM in the lung. Dietary supplementation with vitamin E or pirfenidone was effective at decreasing AM-induced pulmonary fibrosis in the hamster, as assessed by hydroxyproline content and histological disease scoring 21 days post-dosing. Both agents decreased pulmonary over-expression of the pro-fibrotic cytokine transforming growth factor (TGF)-[beta]1 following AM administration, suggesting a possible mechanism of their protective profiles. However, neither vitamin E nor pirfenidone supplementation was able to prevent AM- and DEA-induced mitochondrial dysfunction 'in vitro', or respiratory inhibition in lung mitochondria isolated following 'in vivo' AM administration. In summary, mitochondrial dysfunction likely plays a role in initiating AM-induced lung cell death that leads to pulmonary fibrosis, and DEA is a more potent and rapid inhibitor of mitochondrial function than AM. Both vitamin E and pirfenidone displayed a protective effect against AIPT in the hamster model, mediated at least in part by their ability to down-regulate TGF-[beta] 1 over-expression following AM treatment while not altering AM- and DEA-induced mitochondrial dysfunction. These agents may prove useful in the treatment of clinical AIPT.
ISBN
0612732878
9780612732872