Regulation of macroautophagy in amiodarone‐induced pulmonary fibrosis

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 pl...

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Published in:The journal of pathology. Clinical research 2015-10, Vol.1 (4), p.252-263
Main Authors: Mahavadi, Poornima, Knudsen, Lars, Venkatesan, Shalini, Henneke, Ingrid, Hegermann, Jan, Wrede, Christoph, Ochs, Matthias, Ahuja, Saket, Chillappagari, Shashi, Ruppert, Clemens, Seeger, Werner, Korfei, Martina, Guenther, Andreas
Format: Article
Language:English
Subjects:
alveolar epithelial cells
Alveoli
Amiodarone
Apoptosis
Autophagy
Benzofuran
Cardiac arrhythmia
Cell culture
Chronic obstructive pulmonary disease
Epithelial cells
Fibrosis
Homeostasis
lamellar bodies
LC3B
Life sciences
Lung diseases
Microscopy
Molecular modelling
Organelles
Original
Phagocytosis
Pulmonary fibrosis
Surfactants
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Summary: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.
ISSN:2056-4538
2056-4538
DOI:10.1002/cjp2.20