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

Area of Science:

• Cell Biology
• Toxicology
• Pharmacology

Background:

• Amiodarone is a widely used antiarrhythmic drug.
• Amiodarone-induced pulmonary toxicity is a severe adverse effect with unclear mechanisms.
• Alveolar epithelial cells are implicated in amiodarone's lung toxicity.

Purpose of the Study:

• To investigate the molecular mechanisms of amiodarone-induced pulmonary toxicity.
• To examine the effects of amiodarone on phospholipidosis and apoptosis in rat alveolar epithelial cells.
• To elucidate the role of specific proteins in amiodarone's cellular effects.

Main Methods:

• Medium-term oral administration of amiodarone (30 mg/kg/day) or vehicle to Wistar rats for two weeks.
• Assessment of apoptosis using terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labeling (TUNEL) assay.
• Immunohistochemical analysis of apoptosis- and phospholipidosis-related proteins, including caspase-8, survivin, Bcl-2, c-Flip, and caspase-3.

Main Results:

• Amiodarone treatment led to phospholipidosis in rat alveolar epithelial cells, characterized by intracellular inclusion bodies.
• Amiodarone decreased phospholipase-C-γ1 and increased phosphatidylinositol-(4,5)-bisphosphate levels.
• While expression of activated-caspase-8 increased and anti-apoptotic proteins (survivin, Bcl-2, c-Flip) decreased, activated-caspase-3 expression was lower, resulting in attenuated apoptosis (fewer TUNEL-positive cells).

Conclusions:

• Medium-term amiodarone administration induces phospholipidosis in rat alveolar epithelial cells.
• Despite a decrease in anti-apoptotic proteins, amiodarone treatment attenuated apoptosis through the caspase-3 pathway.
• These findings contribute to understanding the mechanisms of amiodarone-induced pulmonary toxicity.