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A Novel Antifibrotic Mechanism of Nintedanib and Pirfenidone. Inhibition of Collagen Fibril Assembly.
Knüppel, Larissa; Ishikawa, Yoshihiro; Aichler, Michaela; Heinzelmann, Katharina; Hatz, Rudolf; Behr, Jürgen; Walch, Axel; Bächinger, Hans Peter; Eickelberg, Oliver; Staab-Weijnitz, Claudia A.
Afiliação
  • Knüppel L; 1 Comprehensive Pneumology Center, and.
  • Ishikawa Y; 2 Department of Biochemistry and Molecular Biology, Oregon Health and Science University, Portland, Oregon.
  • Aichler M; 3 Research Department, Shriners Hospital for Children, Portland, Oregon.
  • Heinzelmann K; 4 Research Unit Analytical Pathology, Helmholtz-Zentrum München, Munich, Germany.
  • Hatz R; 1 Comprehensive Pneumology Center, and.
  • Behr J; 5 Thoraxchirurgisches Zentrum, Klinik für Allgemeine-, Viszeral-, Transplantations-, Gefäß- und Thoraxchirurgie, Klinikum Großhadern, and.
  • Walch A; 6 Asklepios Fachkliniken München-Gauting, Munich, Germany; and.
  • Bächinger HP; 7 Medizinische Klinik und Poliklinik V, Klinikum der Ludwig-Maximilians-Universität, Ludwig-Maximilians-Universität, Munich, Germany.
  • Eickelberg O; 6 Asklepios Fachkliniken München-Gauting, Munich, Germany; and.
  • Staab-Weijnitz CA; 4 Research Unit Analytical Pathology, Helmholtz-Zentrum München, Munich, Germany.
Am J Respir Cell Mol Biol ; 57(1): 77-90, 2017 07.
Article em En | MEDLINE | ID: mdl-28257580
Idiopathic pulmonary fibrosis (IPF) is characterized by excessive deposition of extracellular matrix, in particular, collagens. Two IPF therapeutics, nintedanib and pirfenidone, decelerate lung function decline, but their underlying mechanisms of action are poorly understood. In this study, we sought to analyze their effects on collagen synthesis and maturation at important regulatory levels. Primary human fibroblasts from patients with IPF and healthy donors were treated with nintedanib (0.01-1.0 µM) or pirfenidone (100-1,000 µM) in the absence or presence of transforming growth factor-ß1. Effects on collagen, fibronectin, FKBP10, and HSP47 expression, and collagen I and III secretion, were analyzed by quantitative polymerase chain reaction and Western blot. The appearance of collagen fibrils was monitored by scanning electron microscopy, and the kinetics of collagen fibril assembly was assessed using a light-scattering approach. In IPF fibroblasts, nintedanib reduced the expression of collagen I and V, fibronectin, and FKBP10 and attenuated the secretion of collagen I and III. Pirfenidone also down-regulated collagen V but otherwise showed fewer and less pronounced effects. By and large, the effects were similar in donor fibroblasts. For both drugs, electron microscopy of IPF fibroblast cultures revealed fewer and thinner collagen fibrils compared with untreated controls. Finally, both drugs dose-dependently delayed fibril formation of purified collagen I. In summary, both drugs act on important regulatory levels in collagen synthesis and processing. Nintedanib was more effective in down-regulating profibrotic gene expression and collagen secretion. Importantly, both drugs inhibited collagen I fibril formation and caused a reduction in and an altered appearance of collagen fibril bundles, representing a completely novel mechanism of action for both drugs.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Colágenos Fibrilares / Fibrose Pulmonar Idiopática / Indóis Idioma: En Ano de publicação: 2017 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Piridonas / Colágenos Fibrilares / Fibrose Pulmonar Idiopática / Indóis Idioma: En Ano de publicação: 2017 Tipo de documento: Article