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

Amiodarone is an antiarrhythmic drug with numerous side effects, the m ost serious being the development of pulmonary toxicity. We-have previ ously reported that a single intratracheal instillation of amiodarone to Fischer 344 rats results in pulmonary fibrosis within 6 wk of treat ment. Presently, the mechanism of amiodarone-induced pulmonary toxicit y is unknown. Cytokines that stimulate fibroblast proliferation and/or collagen production may play a role in amiodarone-induced pulmonary t oxicity. To investigate this possibility, female rats were given a sin gle intratracheal instillation of amiodarone (6.25 mg/kg), ifs metabol ite desethylamiodarone (5 mg/kg), or vehicle (sterile water). At 1, 2, 3, or 6 wk after treatment the lungs were lavaged and the recovered c ells were counted and identified. The alveolar macrophages were isolat ed 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. Desethylamiodaron e treatment resulted in a neutrophilic alveolitis, but the levels of T NF-alpha and TGF-beta were not significantly different from control an imals. In contrast, amiodarone treatment resulted in a lymphocytic alv eolitis 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 value s were not significantly different from those of controls. In conclusi on, the release of TNF-alpha may play a role in the development of ami odarone-induced pulmonary toxicity.