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Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology 06 Biological Sciences 0601 Biochemistry and Cell Biology

Lehmann, Mareike; Buhl, Lara; Alsafadi, Hani N. LU ; Klee, Stephan; Hermann, Sarah; Mutze, Kathrin; Ota, Chiharu; Lindner, Michael; Behr, Jürgen and Hilgendorff, Anne, et al. (2018) In Respiratory Research 19(1).
Abstract

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. Methods: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with... (More)

Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. Methods: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. Results: Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. Conclusions: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.

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published
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keywords
ATII, Epithelial cells, ex vivo, IPF, Lung disease, Nintedanib, PCLS, Pirfenidone
in
Respiratory Research
volume
19
issue
1
publisher
BioMed Central
external identifiers
  • scopus:85053381690
ISSN
1465-9921
DOI
10.1186/s12931-018-0876-y
language
English
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yes
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10e39add-0506-4bfa-b159-c71057f8277c
date added to LUP
2018-10-11 09:10:48
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2019-03-17 05:09:27
@article{10e39add-0506-4bfa-b159-c71057f8277c,
  abstract     = {<p>Background: Idiopathic pulmonary fibrosis (IPF) is a fatal interstitial lung disease. Repetitive injury and reprogramming of the lung epithelium are thought to be critical drivers of disease progression, contributing to fibroblast activation, extracellular matrix remodeling, and subsequently loss of lung architecture and function. To date, Pirfenidone and Nintedanib are the only approved drugs known to decelerate disease progression, however, if and how these drugs affect lung epithelial cell function, remains largely unexplored. Methods: We treated murine and human 3D ex vivo lung tissue cultures (3D-LTCs; generated from precision cut lung slices (PCLS)) as well as primary murine alveolar epithelial type II (pmATII) cells with Pirfenidone or Nintedanib. Murine 3D-LTCs or pmATII cells were derived from the bleomycin model of fibrosis. Early fibrotic changes were induced in human 3D-LTCs by a mixture of profibrotic factors. Epithelial and mesenchymal cell function was determined by qPCR, Western blotting, Immunofluorescent staining, and ELISA. Results: Low μM concentrations of Nintedanib (1 μM) and mM concentrations of Pirfenidone (2.5 mM) reduced fibrotic gene expression including Collagen 1a1 and Fibronectin in murine and human 3D-LTCs as well as pmATII cells. Notably, Nintedanib stabilized expression of distal lung epithelial cell markers, especially Surfactant Protein C in pmATII cells as well as in murine and human 3D-LTCs. Conclusions: Pirfenidone and Nintedanib exhibit distinct effects on murine and human epithelial cells, which might contribute to their anti-fibrotic action. Human 3D-LTCs represent a valuable tool to assess anti-fibrotic mechanisms of potential drugs for the treatment of IPF patients.</p>},
  articleno    = {175},
  author       = {Lehmann, Mareike and Buhl, Lara and Alsafadi, Hani N. and Klee, Stephan and Hermann, Sarah and Mutze, Kathrin and Ota, Chiharu and Lindner, Michael and Behr, Jürgen and Hilgendorff, Anne and Wagner, Darcy E. and Königshoff, Melanie},
  issn         = {1465-9921},
  keyword      = {ATII,Epithelial cells,ex vivo,IPF,Lung disease,Nintedanib,PCLS,Pirfenidone},
  language     = {eng},
  month        = {09},
  number       = {1},
  publisher    = {BioMed Central},
  series       = {Respiratory Research},
  title        = {Differential effects of Nintedanib and Pirfenidone on lung alveolar epithelial cell function in ex vivo murine and human lung tissue cultures of pulmonary fibrosis 11 Medical and Health Sciences 1102 Cardiorespiratory Medicine and Haematology 06 Biological Sciences 0601 Biochemistry and Cell Biology},
  url          = {http://dx.doi.org/10.1186/s12931-018-0876-y},
  volume       = {19},
  year         = {2018},
}