Pneumologie 2014; 68 - A32
DOI: 10.1055/s-0034-1376801

Regulation of macroautophagy in amiodarone induced pulmonary fibrosis

P Mahavadi 1, 7, I Henneke 1, L Knudsen 2, 6, S Venkatesan 1, C Ruppert 1, 7, J Hegermann 2, 6, G Liebisch 3, C Wrede 2, 6, R Chambers 4, M Ochs 2, 6, G Schmitz 3, C Vancheri 5, W Seeger 1, 7, M Korfei 1, A Guenther 1, 7
  • 1Justus-Liebig-University Gießen, Gießen
  • 2Hannover Medical School, Hannover
  • 3University of Regensburg, Regensburg
  • 4University College London, London, UK
  • 5University of Catania, Catania, Italy
  • 6Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH)
  • 7University of Gießen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research

Amiodarone (AD) is a highly efficient antiarrhythmic drug, however, it may cause interstitial pneumonia as well as lung fibrosis. Apoptosis of alveolar epithelial type II cells (AECII) has been suggested to play an important role in this disease, but the precise molecular mechanisms are unclear. Here, we aimed to establish a murine model of AD induced lung fibrosis and assess the role of autophagy. Intratracheal administration of AD induced extensive lung fibrosis, accumulation of surfactant phospholipids and surfactant proteins (SP) in mice. Induction of autophagy and apoptosis were encountered in AECII of AD treated mice over time. AD treated MLE12 and primary AECII showed increased proSP-C and LC3B positive vacuolar structures and underwent apoptosis in dependency of LC3B. In vitro, AD induced autophagosome-lysosome fusion and increased the autophagy flux. In vivo, LC3B was localized at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in the AECII. Our data suggest that AD causes activation of macroautophagy, intracellular surfactant accumulation in the AECII and extensive AECII apoptosis, resulting in lung fibrosis.