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Intratracheal amiodarone administration to F344 rats directly damages lung airway and parenchymal cells.

Authors
Taylor-MD; Antonini-JM; Roberts-JR; Leonard-SS; Shi-X; Gannett-PM; Hubbs-AF; Reasor-MJ
Source
Toxicol Appl Pharmacol 2003 Apr; 188(2):92-103
NIOSHTIC No.
20023688
Abstract
Amiodarone (AD) is gaining support as a first-line antiarrhythmic drug despite its potentially fatal pulmonary toxicity involving inflammation and fibrosis. We previously reported a model for this amiodarone-induced pulmonary toxicity (AIPT) in which F344 rats were intratracheally (i.t.) instilled with AD (6.25 mg/kg) in sterile water on days 0 and 2, which led to transient pulmonary inflammation and lung damage and subsequent fibrosis. The goals of this study were to determine the direct effect of the drug in the lung damage occurring after i.t. AD administration, to identify its location, and to examine its potential mechanisms. Using bronchoalveolar lavage and laser-scanning confocal microscopy, it was discovered that AD instillation produces rapid and massive damage to the alveolar-capillary barrier and damage or death to lung airway and parenchymal cells. While AD in solution was found to be capable of generating hydroxyl radicals, protection from AD-induced damage could not be obtained by incorporating water-soluble antioxidants in the drug solution. However, damage induced by free-radicals could still occur after AD partitions into lipid membranes. AD could also be directly disrupting cellular membranes via its amphiphilic structure. It is not known if the mechanism(s) of damage following i.t. AD treatment are similar to the mechanisms that underlie human AIPT. Therefore these data suggest that investigators should use caution in extrapolating results from animal studies that utilize i.t. administration of AD to human AIPT.
Keywords
Pulmonary-system; Pulmonary-system-disorders; In-vitro-studies; Animal-studies; Lung-disease; Lung-disorders; Laboratory-animals; Respiratory-system-disorders
Contact
National Institute for Occupational Safety and Health, Health Effects Laboratory Division, 1095 Willowdale Road, M/S 2015, Morgantown, WV 26505
CODEN
TXAPA9
Publication Date
20030415
Document Type
Journal Article
Email Address
MDTaylor@cdc.gov
Fiscal Year
2003
NTIS Accession No.
NTIS Price
Issue of Publication
2
ISSN
0041-008X
NIOSH Division
HELD
Priority Area
Work Environment and Workforce: Mixed Exposures
Source Name
Toxicology and Applied Pharmacology
State
WV
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