Amiodarone attenuates apoptosis, but induces phospholipidosis in rat alveolar epithelial cells (Journal article)

Kapatou, E./ Skyrlas, A./ Agelaki, M. G./ Pantos, C./ Kolettis, T. M./ Malamou-Mitsi, V.

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-gamma1 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.
Institution and School/Department of submitter: Πανεπιστήμιο Ιωαννίνων. Σχολή Επιστημών Υγείας. Τμήμα Ιατρικής
Keywords: Amiodarone/*pharmacology,Animals,Apoptosis/*drug effects,Apoptosis Regulatory Proteins/antagonists & inhibitors/genetics/metabolism,Caspase 3/antagonists & inhibitors/genetics/metabolism,Caspase 8/genetics/metabolism,Epithelial Cells/drug effects/metabolism,Female,In Situ Nick-End Labeling/methods,Lipidoses/chemically induced/metabolism,Lung/cytology/drug effects/metabolism,Phosphatidylinositol 4,5-Diphosphate/genetics/metabolism,Phospholipase C gamma/genetics/metabolism,Phospholipids/*biosynthesis,Pulmonary Alveoli/cytology/*drug effects/metabolism,Rats,Rats, Wistar
ISSN: 1899-1505
Appears in Collections:Άρθρα σε επιστημονικά περιοδικά ( Ανοικτά)

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