Transcriptome profiling reveals the complexity of pirfenidone effects in IPF

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 analyzed 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.