title: Activation of autophagy rescues amiodarone-induced apoptosis of lung epithelial cells and pulmonary toxicity in rats.
abstract: Amiodarone, bi-iodinated benzofuran derivative, is one of the most frequently prescribed and efficacious antiarrhythmic drugs. Despite its low incidence, amiodarone-induced pulmonary toxicity is of great concern and the leading cause of discontinuation. Autophagy is an essential homeostatic process that mediates continuous recycling of intracellular materials when nutrients are scarce. It either leads to a survival advantage or initiates death processes in cells under stress. In the present study, we investigated the role of autophagy in amiodarone-induced pulmonary toxicity. Amiodarone treatment-induced autophagy in H460 human lung epithelial cells and BEAS-2B normal human bronchial epithelial cells was demonstrated by increased LC3-II conversion, Atg7 upregulation, and autophagosome formation. Autophagic flux, as determined by the lysosomal inhibitor bafilomycin A1, was also increased following amiodarone treatment. To determine the role of autophagy in amiodarone toxicity, amiodarone-induced cell death was evaluated in the presence of 3-methyladenine or by knocking down the autophagy-related genes Atg7. Inhibition of autophagy decreased cellular viability and significantly increased apoptosis. Intratracheal instillation of amiodarone in rats increased the number of inflammatory cells recovered from bronchoalveolar lavage fluid, and periodic acid-Schiff-positive staining in bronchiolar epithelial cells. However, induction of autophagy by rapamycin treatment inhibited amiodarone-induced pulmonary toxicity. In conclusion, amiodarone treatment induced autophagy, which is involved in protection against cell death and pulmonary toxicity.
authors.affiliation: * College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, 151-742, Republic of Korea;
authors.forename: Kang-Yo
authors.initials: KY
authors.lastname: Lee
authors.forename: Sehee
authors.initials: S
authors.lastname: Oh
authors.forename: You-Jin
authors.initials: YJ
authors.lastname: Choi
authors.forename: Seon-Hee
authors.initials: SH
authors.lastname: Oh
authors.forename: Young-Su
authors.initials: YS
authors.lastname: Yang
authors.forename: Mi-Jin
authors.initials: MJ
authors.lastname: Yang
authors.forename: Kyuhong
authors.initials: K
authors.lastname: Lee
authors.forename: Byung-Hoon
authors.initials: BH
authors.lastname: Lee
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000280:Administration, Inhalation; D000638:Amiodarone / Q000008:administration & dosage / Q000633:toxicity*; D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000008:administration & dosage / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D000071193:Autophagy-Related Protein 7; D001992:Bronchoalveolar Lavage Fluid / Q000276:immunology; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D055785:Gene Knockdown Techniques; D006801:Humans; D008168:Lung / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018942:Macrolides / Q000494:pharmacology; D008297:Male; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D051381:Rats; D011916:Rats, Inbred F344; D015398:Signal Transduction / Q000187:drug effects; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D044764:Ubiquitin-Activating Enzymes / Q000378:metabolism
chemical_list: D000889:Anti-Arrhythmia Agents; C477012:MAP1LC3A protein, human; D018942:Macrolides; D008869:Microtubule-Associated Proteins; C025946:3-methyladenine; C040929:bafilomycin A1; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C509349:ATG7 protein, human; D000071193:Autophagy-Related Protein 7; D044764:Ubiquitin-Activating Enzymes; D000225:Adenine; D000638:Amiodarone; D020123:Sirolimus
keywords: amiodarone; apoptosis; autophagy; pulmonary toxicity.