Activation of autophagy rescues amiodarone-induced apoptosis of lung epithelial cells and pulmonary toxicity in rats.
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.
['Lee|Kang-Yo|KY|', 'Oh|Sehee|S|', 'Choi|You-Jin|YJ|', 'Oh|Seon-Hee|SH|', 'Yang|Young-Su|YS|', 'Yang|Mi-Jin|MJ|', 'Lee|Kyuhong|K|', 'Lee|Byung-Hoon|BH|']
D000225:Adenine D000280:Administration, Inhalation D000638:Amiodarone D000818:Animals D000889:Anti-Arrhythmia Agents D017209:Apoptosis D001343:Autophagy D000071193:Autophagy-Related Protein 7 D001992:Bronchoalveolar Lavage Fluid D002460:Cell Line D002470:Cell Survival D004305:Dose-Response Relationship, Drug D004847:Epithelial Cells D055785:Gene Knockdown Techniques D006801:Humans D008168:Lung D018942:Macrolides D008297:Male D008869:Microtubule-Associated Proteins D051057:Proto-Oncogene Proteins c-akt D034622:RNA Interference D051381:Rats D011916:Rats, Inbred F344 D015398:Signal Transduction D020123:Sirolimus D058570:TOR Serine-Threonine Kinases D013997:Time Factors D014162:Transfection D044764:Ubiquitin-Activating Enzymes
autophagy apoptosis amiodarone pulmonary toxicity.