Attenuation of amiodarone-induced pulmonary fibrosis by vitamin E is associated with suppression of transforming growth factor-beta1 gene expression but not prevention of mitochondrial dysfunction.
Amiodarone (AM) is an efficacious antidysrhythmic agent that can cause numerous adverse effects, including potentially life-threatening pulmonary fibrosis. The current study was undertaken to investigate potential protective mechanisms of vitamin E against AM-induced pulmonary toxicity (AIPT) in the hamster. Three weeks after intratracheal administration of AM (1.83 micromol), increased pulmonary hydroxyproline content and histological damage were observed, indicative of fibrosis. These effects were preceded by increased pulmonary levels of transforming growth factor (TGF)-beta1 mRNA at 1 week post-AM, which remained elevated 3 weeks post-AM. Dietary supplementation with vitamin E resulted in rapid pulmonary accumulation of the vitamin, and prevention of AM-induced increases in TGF-beta1, hydroxyproline, and histological damage. Although dietary supplementation also markedly elevated lung mitochondrial vitamin E content, it did not attenuate AM-induced inhibition of mitochondrial respiration or disruption of mitochondrial membrane potential in vitro, or lung mitochondrial respiratory inhibition resulting from in vivo AM administration. These results suggest that vitamin E reduces the extent of pulmonary damage after AM administration via down-regulating TGF-beta1 overexpression but that it does not modify AM-induced mitochondrial dysfunction, a potential initiating event in AIPT.
Card
Jeffrey W
JW
Department of Pharmacology and Toxicology, Faculty of Health Sciences, Queen's University, Kingston, Ontario, Canada.
Racz
William J
WJ
Brien
James F
JF
Massey
Thomas E
TE
D000638:Amiodarone / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000037:antagonists & inhibitors* / Q000633:toxicity*; D000975:Antioxidants / Q000494:pharmacology*; D006224:Cricetinae; D015342:DNA Probes; D004032:Diet; D015870:Gene Expression / Q000187:drug effects*; D006909:Hydroxyproline / Q000378:metabolism; D017403:In Situ Hybridization; D008168:Lung / Q000737:chemistry / Q000473:pathology; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008647:Mesocricetus; D008928:Mitochondria / Q000187:drug effects*; D010101:Oxygen Consumption; D011048:Polarography; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D012333:RNA, Messenger / Q000096:biosynthesis; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000235:genetics; D053773:Transforming Growth Factor beta1; D014810:Vitamin E / Q000494:pharmacology*
D000889:Anti-Arrhythmia Agents; D000975:Antioxidants; D015342:DNA Probes; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D014810:Vitamin E; C036116:desethylamiodarone; D000638:Amiodarone; D006909:Hydroxyproline