Amiodarone attenuates apoptosis,but induces phospholipidosis in rat alveolar epithelial cells

Amiodarone-induced pulmonary toxicity is a serious side-effect,but the underlying molecular mechanisms remain unclear. we examined phospholipidosis and apoptosis in rat alveolar epithelial cells after medium-term oral amiodarone treatment. amiodarone (30 mg/kg daily,a dosage corresponding to that used clinically) or vehicle was administered by gavage in 33 wistar rats for two weeks. apoptosis was assessed by terminal deoxynucleotidyl transferase (tdt)- mediated dutp nick end-labelling (tunel) and the expression of apoptosis- and phospholipidosis-related proteins was measured by immunohistochemistry. amiodarone decreased phospholipase-c-γ1 and increased phosphatidylinositol-(4,5)-bisphosphate,resulting in phospholipidosis,evidenced by the appearance of intracellular inclusion bodies with a multi-lamellated interior. amiodarone exerted two opposite effects on apoptosis; compared to controls,the expression of activated-caspase-8 was higher in treated rats,while the expression of apoptosis inhibitors survivin,bcl-2 and c-flip was lower. on the other hand,the expression of activated-caspase-3 was lower after treatment. overall,amiodarone attenuated apoptosis,evidenced by fewer tunel-positive cells. medium-term oral amiodarone administration induced phospholipidosis in rat alveolar epithelial cells. although such treatment decreased anti-apoptotic proteins,apoptosis was attenuated via a decrease in the caspase-3 pathway. these findings improve current understanding on the mechanisms underlying amiodarone-induced pulmonary toxicity.