Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis

Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF), it remains unclear if lung fibroblasts (FB) are the main therapeutic target.To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and FB derived from IPF patients treated with or without pirfenidone.In FB, pirfenidone therapy predominantly affected growth and cell division pathways, indicating a major cellular metabolic shift. In LH samples, pirfenidone treatment was mostly associated with inflammation-related processes. In FB and LH, regulated genes were over-represented in the Gene Ontology node "extracellular matrix". We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated IPF patients. Plasma levels of CEMIP were elevated in IPF patients compared to healthy controls and decreased after 7 months of pirfenidone treatment. CEMIP expression in FB was downregulated in a glioma-associated oncogene homologue-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration.Cumulatively, our approach indicates that pirfenidone exerts beneficial effects via its action on multiple pathways in both FB and other pulmonary cells, through its ability to control extracellular matrix architecture and inflammatory reactions.

  • Kwapiszewska, G.
  • Gungl, A.
  • Wilhelm, J.
  • Marsh, L. M.
  • Thekkekara Puthenparampil, H.
  • Sinn, K.
  • Didiasova, M.
  • Klepetko, W.
  • Kosanovic, D.
  • Schermuly, R. T.
  • Wujak, L.
  • Weiss, B.
  • Schaefer, L.
  • Schneider, M.
  • Kreuter, M.
  • Olschewski, A.
  • Seeger, W.
  • Olschewski, H.
  • Wygrecka, M.

Keywords

  • Adult
  • Aged
  • Cell Movement/drug effects
  • Cell Proliferation/drug effects
  • Down-Regulation/genetics
  • Extracellular Matrix/metabolism
  • Female
  • Fibroblasts/drug effects/metabolism
  • Gene Expression Profiling
  • Gene Ontology
  • Humans
  • Hyaluronoglucosaminidase
  • Idiopathic Pulmonary Fibrosis/*drug therapy/*genetics
  • Lung/pathology
  • Male
  • Middle Aged
  • Proteins/*metabolism
  • Pyridones/*therapeutic use
  • Transcriptome
  • from Pfizer, outside the submitted work. Conflict of interest: W. Seeger reports
  • personal fees from Pfizer, Novartis, United Therapeutics, Actelion, Vectura,
  • Savara, Medspray and Bayer AG, outside the submitted work. Conflict of interest:
  • H. Olschewski reports grants from Intermune/Roche, and grants and personal fees
  • from Boehringer, outside the submitted work. All other authors have nothing to
  • disclose.
Publication details
DOI: 10.1183/13993003.00564-2018
Journal: Eur Respir J
Number: 5
Work Type: Original
Access number: 30166321
See publication on PubMed
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