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Mahavadi P, Knudsen L, Venkatesan S, et al. Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis. J Pathol Clin Res. 2015;1(4):252-63doi: 10.1002/cjp2.20.
Mahavadi, P., Knudsen, L., Venkatesan, S., Henneke, I., Hegermann, J., Wrede, C., Ochs, M., Ahuja, S., Chillappagari, S., Ruppert, C., Seeger, W., Korfei, M., & Guenther, A. (2015). Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis. The journal of pathology. Clinical research, 1(4), 252-63. https://doi.org/10.1002/cjp2.20
Mahavadi, Poornima, et al. "Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis." The journal of pathology. Clinical research vol. 1,4 (2015): 252-63. doi: https://doi.org/10.1002/cjp2.20
Mahavadi P, Knudsen L, Venkatesan S, Henneke I, Hegermann J, Wrede C, Ochs M, Ahuja S, Chillappagari S, Ruppert C, Seeger W, Korfei M, Guenther A. Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis. J Pathol Clin Res. 2015 Jun 03;1(4):252-63. doi: 10.1002/cjp2.20. eCollection 2015 Oct. PMID: 27499909; PMCID: PMC4939895.
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J Pathol Clin Res. 2015 Jun 03;1(4):252-63. doi: 10.1002/cjp2.20. eCollection 2015 Oct.

Regulation of macroautophagy in amiodarone-induced pulmonary fibrosis.

The journal of pathology. Clinical research

Poornima Mahavadi, Lars Knudsen, Shalini Venkatesan, Ingrid Henneke, Jan Hegermann, Christoph Wrede, Matthias Ochs, Saket Ahuja, Shashi Chillappagari, Clemens Ruppert, Werner Seeger, Martina Korfei, Andreas Guenther

Affiliations

  1. Department of Internal MedicineJustus-Liebig-UniversityGiessenGermany; Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany.
  2. 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.
  3. Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL)GiessenGermany; Department of Medicine, Pulmonary Critical CarePhilipps-Universität MarburgBaldingerstrasse 135043MarburgGermany.
  4. 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.
  5. 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.

PMID: 27499909 PMCID: PMC4939895 DOI: 10.1002/cjp2.20

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.

Keywords: LC3B; alveolar epithelial cells; amiodarone; apoptosis; autophagy; lamellar bodies

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