title: Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis.
abstract: Amiodarone (AD) is an iodinated benzofuran derivative, especially known for its antiarrhythmic properties. It exerts serious side-effects even in patients receiving low doses. AD is well-known to induce apoptosis of type II alveolar epithelial cells (AECII), a mechanism that has been suggested to play an important role in AD-induced lung fibrosis. The precise molecular mechanisms underlying this disease are, however, still unclear. Because of its amphiphilic nature, AD becomes enriched in the lysosomal compartments, affecting the general functions of these organelles. Hence, in this study, we aimed to assess the role of autophagy, a lysosome-dependent homeostasis mechanism, in driving AECII apoptosis in response to AD. In vitro, AD-treated MLE12 and primary AECII cells showed increased proSP-C and LC3B positive vacuolar structures and underwent LC3B-dependent apoptosis. In addition, AD-induced autophagosome-lysosome fusion and increased autophagy flux were observed. In vivo, in C57BL/6 mice, LC3B was localised at the limiting membrane of lamellar bodies, which were closely connected to the autophagosomal structures in AECIIs. Our data suggest that AD causes activation of macroautophagy in AECIIs and extensive autophagy-dependent apoptosis of alveolar epithelial cells. Targeting the autophagy pathway may therefore represent an attractive treatment modality in AD-induced lung fibrosis.
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Poornima
authors: P
authors: Mahavadi
authors: Institute of Functional and Applied Anatomy, Hannover Medical SchoolHannoverGermany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL)HannoverGermany; REBIRTH Cluster of ExcellenceHannoverGermany.
authors: Lars
authors: L
authors: Knudsen
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Shalini
authors: S
authors: Venkatesan
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Ingrid
authors: I
authors: Henneke
authors: Institute of Functional and Applied Anatomy, Hannover Medical SchoolHannoverGermany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL)HannoverGermany; REBIRTH Cluster of ExcellenceHannoverGermany.
authors: Jan
authors: J
authors: Hegermann
authors: Institute of Functional and Applied Anatomy, Hannover Medical SchoolHannoverGermany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL)HannoverGermany; REBIRTH Cluster of ExcellenceHannoverGermany.
authors: Christoph
authors: C
authors: Wrede
authors: Institute of Functional and Applied Anatomy, Hannover Medical SchoolHannoverGermany; Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), German Center for Lung Research (DZL)HannoverGermany; REBIRTH Cluster of ExcellenceHannoverGermany.
authors: Matthias
authors: M
authors: Ochs
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Saket
authors: S
authors: Ahuja
authors: Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany; Department of Medicine, Pulmonary Critical CarePhilipps-Universität MarburgBaldingerstrasse 135043MarburgGermany.
authors: Shashi
authors: S
authors: Chillappagari
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Clemens
authors: C
authors: Ruppert
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany; Member of the European IPF Network.
authors: Werner
authors: W
authors: Seeger
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
authors: Martina
authors: M
authors: Korfei
authors: Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany; Member of the European IPF Network; Lung Clinic Waldhof-ElgershausenGreifensteinGermany.
authors: Andreas
authors: A
authors: Guenther
keywords: LC3B; alveolar epithelial cells; amiodarone; apoptosis; autophagy; lamellar bodies