title: Amiodarone-induced pulmonary toxicity in Fischer rats: release of tumor necrosis factor alpha and transforming growth factor beta by pulmonary alveolar macrophages.
abstract: Amiodarone is an antiarrhythmic drug with numerous side effects, the most serious being the development of pulmonary toxicity. We have previously reported that a single intratracheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treatment. Presently, the mechanism of amiodarone-induced pulmonary toxicity is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary toxicity. To investigate this possibility, female rats were given a single intratracheal instillation of amiodarone (6.25 mg/kg), its metabolite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At 1, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identified. The alveolar macrophages were isolated by attachment to plastic petri dishes, cultured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-alpha) and transforming growth factor beta (TGF-beta) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-alpha and TGF-beta were not significantly different from control animals. In contrast, amiodarone treatment resulted in a lymphocytic alveolitis and significantly higher amounts of TNF-alpha were observed at 3 and 6 wk after treatment. A trend toward higher levels of TGF-beta was also noted in the amiodarone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-alpha may play a role in the development of amiodarone-induced pulmonary toxicity.
authors.affiliation: Graduate Center for Toxicology, University of Kentucky, Lexington, USA.
authors.forename: P G
authors.initials: PG
authors.lastname: Reinhart
authors.forename: C G
authors.initials: CG
authors.lastname: Gairola
mesh_terms: D000638:Amiodarone / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D002452:Cell Count; D002478:Cells, Cultured; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D011916:Rats, Inbred F344; D014132:Trachea; D016212:Transforming Growth Factor beta / Q000032:analysis / Q000378:metabolism*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000378:metabolism*
chemical_list: D000889:Anti-Arrhythmia Agents; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C036116:desethylamiodarone; D000638:Amiodarone