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Knüppel, L. ; Ishikawa, Y.* ; Aichler, M. ; Heinzelmann, K. ; Hatz, R.* ; Behr, J.* ; Walch, A.K. ; Bächinger, H.P.* ; Eickelberg, O. ; Staab-Weijnitz, C.A.

A novel antifibrotic mechanism of nintedanib and pirfenidone: Inhibition of collagen fibril assembly.

Am. J. Respir. Cell Mol. Biol. 57, 77-90 (2017)
Verlagsversion Postprint Forschungsdaten DOI
Open Access Green
RATIONALE: 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. METHODS: Primary human fibroblasts from IPF patients and healthy donors were treated with nintedanib (0.01-1.0µM) or pirfenidone (0.1-1.0mM) in absence or presence of TGF-β1. Effects on collagen, fibronectin, FKBP10, HSP47 expression and collagen I and III secretion were analyzed by qPCR and Western Blot. Appearance of collagen fibrils was monitored by scanning electron microscopy (SEM) and kinetics of collagen fibril assembly was assessed in a light scattering approach. RESULTS: In IPF fibroblasts, nintedanib reduced the expression of collagen I, V, fibronectin and FKBP10 and attenuated secretion of collagen I and III. Pirfenidone also downregulated collagen V, but otherwise showed fewer and less pronounced effects. By and large, 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. CONCLUSIONS: Both drugs act on important regulatory levels in collagen synthesis and processing. Nintedanib was more effective in downregulating profibrotic gene expression and collagen secretion. Importantly, both drugs inhibited collagen I fibril formation and caused reduction and an altered appearance of collagen fibril bundles, representing a completely novel mechanism of action for both drugs.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Idiopathic Pulmonary Fibrosis ; Extracellular Matrix ; Nintedanib ; Pirfenidone; Idiopathic Pulmonary-fibrosis; Collagen Fibril Formation; Shock-protein 47; Extracellular-matrix; Endoplasmic-reticulum; Lung Fibroblasts; Growth-factor; In-vitro; Osteogenesis Imperfecta; Cross-linking
ISSN (print) / ISBN 1044-1549
e-ISSN 1535-4989
Zeitschrift American Journal of Respiratory Cell and Molecular Biology
Quellenangaben Band: 57, Heft: 1, Seiten: 77-90 Artikelnummer: , Supplement: ,
Verlag American Thoracic Society
Verlagsort New York
Begutachtungsstatus