title: Amiodarone attenuates apoptosis, but induces phospholipidosis in rat alveolar epithelial cells.
abstract: 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.
authors.affiliation: Department of Pathology, University of Ioannina Medical School, Ioannina, Greece.
authors.forename: E
authors.initials: E
authors.lastname: Kapatou
authors.forename: A
authors.initials: A
authors.lastname: Skyrlas
authors.forename: M G
authors.initials: MG
authors.lastname: Agelaki
authors.forename: C
authors.initials: C
authors.lastname: Pantos
authors.forename: T M
authors.initials: TM
authors.lastname: Kolettis
authors.forename: V
authors.initials: V
authors.lastname: Malamou-Mitsi
mesh_terms: D000638:Amiodarone / Q000494:pharmacology*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D051017:Apoptosis Regulatory Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D053148:Caspase 3 / Q000235:genetics / Q000378:metabolism; D053181:Caspase 8 / Q000235:genetics / Q000378:metabolism; D061945:Caspase Inhibitors; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D005260:Female; D020287:In Situ Nick-End Labeling / Q000379:methods; D008064:Lipidoses / Q000139:chemically induced / Q000378:metabolism; D008168:Lung / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D019269:Phosphatidylinositol 4,5-Diphosphate / Q000235:genetics / Q000378:metabolism; D051966:Phospholipase C gamma / Q000235:genetics / Q000378:metabolism; D010743:Phospholipids / Q000096:biosynthesis*; D011650:Pulmonary Alveoli / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar
chemical_list: D051017:Apoptosis Regulatory Proteins; D061945:Caspase Inhibitors; D019269:Phosphatidylinositol 4,5-Diphosphate; D010743:Phospholipids; D051966:Phospholipase C gamma; D053148:Caspase 3; D053181:Caspase 8; D000638:Amiodarone