%0 Journal Article %A Grazyna Kwapiszewska %A Anna Gungl %A Jochen Wilhelm %A Leigh M. Marsh %A Helene Thekkekara Puthenparampil %A Katharina Sinn %A Miroslava Didiasova %A Walter Klepetko %A Djuro Kosanovic %A Ralph T. Schermuly %A Lukasz Wujak %A Benjamin Weiss %A Liliana Schaefer %A Marc Schneider %A Michael Kreuter %A Andrea Olschewski %A Werner Seeger %A Horst Olschewski %A Malgorzata Wygrecka %T Transcriptome profiling reveals the complexity of pirfenidone effects in IPF %D 2018 %R 10.1183/13993003.00564-2018 %J European Respiratory Journal %P 1800564 %X Despite the beneficial effects of pirfenidone in treating idiopathic pulmonary fibrosis (IPF) patients, it remains unclear if lung fibroblasts are the main therapeutic target. To resolve this question, we employed a comparative transcriptomic approach and analysed lung homogenates (LH) and lung fibroblasts (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 (ECM)”. We identified lower expression of cell migration-inducing and hyaluronan-binding protein (CEMIP) in both LH and FB from pirfenidone-treated 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 homolog (GLI)-dependent manner and CEMIP silencing in IPF FB reduced collagen production and attenuated cell proliferation and migration. Cumulatively, our approach indicates that pirfenidone exerts the beneficial effects via its action on multiple pathways in both fibroblasts and other pulmonary cells, through its ability to control ECM architecture and inflammatory reactions.Pirfenidone mode of action in human lungs involves a complex interactome comprising genes related to inflammation and extracellular matrix architecture.FootnotesThis manuscript has recently been accepted for publication in the European Respiratory Journal. It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article.Conflict of interest: Dr. Kwapiszewska has nothing to disclose.Conflict of interest: Dr. Gungl has nothing to disclose.Conflict of interest: Dr. Wilhelm has nothing to disclose.Conflict of interest: Dr. Marsh has nothing to disclose.Conflict of interest: Thekkekara Puthenparampil has nothing to disclose.Conflict of interest: Dr. Sinn has nothing to disclose.Conflict of interest: Dr. Didiasova has nothing to disclose.Conflict of interest: Dr. Klepetko has nothing to disclose.Conflict of interest: Dr. Kosanovic has nothing to disclose.Conflict of interest: Schermuly no disclosures.Conflict of interest: Dr. Wujak has nothing to disclose.Conflict of interest: Dr. Weiss has nothing to disclose.Conflict of interest: Dr. Schaefer has nothing to disclose.Conflict of interest: Dr. Marc Schneider has nothing to disclose.Conflict of interest: Dr. Michael Kreuter has nothing to disclose.Conflict of interest: Dr. Andrea Olschewski reports grants and other from Pfizer, outside the submitted work.Conflict of interest: Dr. Seeger reports personal fees from Pfizer, personal fees from Novartis, personal fees from United Therapeutics, personal fees from Actelion, personal fees from Vectura, personal fees from Savara, personal fees from Medspray, personal fees from Bayer AG, outside the submitted work.Conflict of interest: Dr. Horst Olschewski reports grants from Intermune/Roche, grants and personal fees from Boehringer, outside the submitted work.Conflict of interest: Dr. Wygrecka has nothing to disclose. %U https://erj.ersjournals.com/content/erj/early/2018/08/09/13993003.00564-2018.full.pdf