RT Journal Article
SR Electronic
T1 Transcriptome profiling reveals the complexity of pirfenidone effects in idiopathic pulmonary fibrosis
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP 1800564
DO 10.1183/13993003.00564-2018
VO 52
IS 5
A1 Grazyna Kwapiszewska
A1 Anna Gungl
A1 Jochen Wilhelm
A1 Leigh M. Marsh
A1 Helene Thekkekara Puthenparampil
A1 Katharina Sinn
A1 Miroslava Didiasova
A1 Walter Klepetko
A1 Djuro Kosanovic
A1 Ralph T. Schermuly
A1 Lukasz Wujak
A1 Benjamin Weiss
A1 Liliana Schaefer
A1 Marc Schneider
A1 Michael Kreuter
A1 Andrea Olschewski
A1 Werner Seeger
A1 Horst Olschewski
A1 Malgorzata Wygrecka
YR 2018
UL http://erj.ersjournals.com/content/52/5/1800564.abstract
AB 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.Pirfenidone's mode of action in human lungs involves a complex interactome comprising genes related to inflammation and extracellular matrix architecture http://ow.ly/26NN30lpGON