AMIODARONE-INDUCED PULMONARY TOXICITY IN FISCHER RATS: RELEASE OF TUMOR NECROSIS FACTOR ALPHA AND TRANSFORMING GROWTH FACTOR BETA BY PULMONARY ALVEOLAR MACROPHAGES

Abstract

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 intratra cheal 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 I, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered cells were counted and identi fied. The alveolar macrophages were isolated by attachment to plastic petri dishes, cul tured overnight, and the spent media collected for tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β) analyses. Desethylamiodarone treatment resulted in a neutrophilic alveolitis, but the levels of TNF-α and TGF-β were not signifi cantly different from control animals. In contrast, amiodarone treatment resulted in a lym phocytic alveolitis and significantly higher amounts of TNF-α were observed at 3 and 6 wk after treatment. A trend toward higher levels of TCF-β was also noted in the amio-darone-treated group at wk 1-3 but the values were not significantly different from those of controls. In conclusion, the release of TNF-α may play a role in the development of amiodarone-induced pulmonary toxicity.