Differential susceptibilities of isolated hamster lung cell types to amiodarone toxicity

Treatment of cardiac dysrhythmias with the iodinated benzofuran derivative amiodarone (AM) is limited by pulmonary toxicity. The susceptibilities of different lung cell types of male Golden Syrian hamsters to AM-induced cytotoxicity were investigated in vitro. Bronchoalveolar lavage and protease digestion to release cells, followed by centrifugal elutriation and density gradient centrifugation, resulted in preparations enriched with alveolar macrophages (98%), alveolar type II cells (75-85%), and nonciliated bronchiolar epithelial (Clara) cells (35-50%). Alveolar type II cell and Clara cell preparations demonstrated decreased viability (by 0.5% trypan blue dye exclusion) when incubated with 50 mu M AM for 36 h, and all AM-treated cell preparations demonstrated decreased viability when incubated with 100 or 200 mu M AM. Based on a viability index ((viability of AM-treated cells divided by viability of controls) x 100%), the Clara cell fraction was significantly (p < 0.05) more susceptible than all of the other cell types to 50 mu M AM. However, AM cytotoxicity was greatest (p < 0.05) in alveolar macrophages following incubation with 100 or 200 mu M AM. There was no difference between any of the enriched cell preparations in the amount of drug accumulated following 24 h of incubation with 50 mu M AM, whereas alveolar macrophages accumulated the most drug during incubation with 100 mu M AM. Thus, the most susceptible cell type was dependent on AM concentration. AM-induced cytotoxicity in specific cell types may initiate processes leading to inflammation and pulmonary fibrosis.