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          Institute: MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut)     Collection: Yearbook_2015     Display Documents



ID: 711887.0, MPI für Herz- und Lungenforschung (W. G. Kerckhoff Institut) / Yearbook_2015
Altered surfactant homeostasis and alveolar epithelial cell stress in amiodarone-induced lung fibrosis
Authors:Mahavadi, P.; Henneke, I.; Ruppert, C.; Knudsen, L.; Venkatesan, S.; Liebisch, G.; Chambers, R. C.; Ochs, M.; Schmitz, G.; Vancheri, C.; Seeger, W.; Korfei, M.; Guenther, A.
Date of Publication (YYYY-MM-DD):2014-11
Title of Journal:Toxicol Sci
Volume:142
Issue / Number:1
Start Page:285
End Page:297
Audience:Not Specified
Abstract / Description:Amiodarone (AD) is a highly efficient antiarrhythmic drug with potentially serious side effects. Severe pulmonary toxicity is reported in patients receiving AD even at low doses and 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. In the current study, we aimed to establish a murine model of AD-induced lung fibrosis and analyze surfactant homeostasis, lysosomal, and endoplasmic reticulum (ER) stress in this model. AD/vehicle was instilled intratracheally into C57BL/6 mice, which were sacrificed on days 7, 14, 21, and 28. Extent of lung fibrosis development was assessed by trichrome staining and hydroxyproline measurement. Cytotoxicity was assessed by lactate dehydrogenase assay. Phospholipids (PLs) were analyzed by mass spectrometry. Surfactant proteins (SP) and markers for apoptosis, lysosomal, and ER stress were studied by Western blotting and immunohistochemistry. AECII morphology was evaluated by electron microscopy. Extensive lung fibrosis and AECII hyperplasia were observed in AD-treated mice already at day 7. Surfactant PL and SP accumulated in AECII over time. In parallel, induction of apoptosis, lysosomal, and ER stress was encountered in AECII of mice lungs and in MLE12 cells treated with AD. In vitro, siRNA-mediated knockdown of cathepsin D did not alter the AD-induced apoptotic response. Our data suggest that mice exposed to intratracheal AD develop severe pulmonary fibrosis, exhibit extensive surfactant alterations and cellular stress, but AD-induced AECII apoptosis is not mediated primarily via cathepsin D.
Free Keywords:ER stress; alveolar epithelial cell apoptosis; amiodarone; lung fibrosis; lysosomal stress; surfactant
External Publication Status:published
Document Type:Article
Communicated by:MPI für Herz- und Lungenforschung
Affiliations:MPI für physiologische und klinische Forschung
External Affiliations:Institute of Functional and Applied Anatomy, Hannover Medical School, Hannover, Germany Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Member of the German Center for Lung Research (DZL), Hannover, Germany REBIRTH Cluster of Excellence, Hannover, Germany. Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany. Centre for Inflammation and Tissue Repair, UCL Respiratory, University College London, London, UK Member of the European IPF Network. Institute of Clinical Chemistry and Laboratory Medicine, University of Regensburg, Regensburg, Germany Member of the European IPF Network. Member of the European IPF Network Department of Clinical and Molecular Biomedicine, University of Catania, Catania 95123, Italy. Department of Internal Medicine, Justus-Liebig-University Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany Member of the European IPF Network. Department of Internal Medicine, Justus-Liebig-University Giessen, Germany Universities of Giessen and Marburg Lung Center (UGMLC), Member of the German Center for Lung Research (DZL), Giessen, Germany Member of the European IPF Network Lung Clinic Waldhof-Elgershausen, Greifenstein, Germany. %^ 1435822045
Identifiers:ISSN:1096-0929 (Electronic) 1096-0929 (Linking) %R 10.1093/toxsci/kfu177
URL:http://www.ncbi.nlm.nih.gov/pubmed/25163675
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