RT Journal Article
SR Electronic
T1 Inhibition of profibrotic signaling in fibroblasts from patients with idiopathic pulmonary fibrosis (IPF) by histone deacetylase-inhibitors (HDACi) or the IPF drug pirfenidone
JF European Respiratory Journal
JO Eur Respir J
FD European Respiratory Society
SP P736
VO 44
IS Suppl 58
A1 Martina Korfei
A1 Sylwia Skwarna
A1 Ingrid Henneke
A1 Oleksiy Klymenko
A1 Gabriele Dahlem
A1 Susanna Ziegler
A1 Daniel von der Beck
A1 Walter Klepetko
A1 Ludger Fink
A1 Werner Seeger
A1 Oliver Krämer
A1 Andreas Guenther
YR 2014
UL http://erj.ersjournals.com/content/44/Suppl_58/P736.abstract
AB Idiopathic pulmonary fibrosis (IPF) is a fatal disease characterized by distorted pulmonary structure and the excessive deposition of extracellular matrix (ECM) proteins, such as collagen. Myofibroblasts are the primary collagen-producing cells in IPF lungs, and their accumulation within lesions called fibroblast foci (FF) is a hallmark of IPF. We investigated the therapeutic potential of histone deacetylase inhibitors (HDACi), because we have discovered a significant overexpression of ClassI/II-HDAC enzymes in IPF fibroblasts/myofibroblasts. Treatment of primary IPF fibroblasts with the pan-HDACi panobinostat (85nmol) resulted in significantly reduced expression of genes associated with fibrogenesis (ACTA2, COL1A1, COL3A1, FN), cell survival (BIRC5), proliferation (CCND1), as well as in suppression of HDAC7, and was paralleled by induction of severe ER Stress (ATF6, CHOP) and apoptosis (p21, PUMA, cleaved caspase-3). Pirfenidone treatment (2.7mM) lead also to a significant downregulation of COL1A1, COL3A1, and FN, but not of ACTA2. The profibrotic genes CNN1 and P4HTM were exclusively reduced by pirfenidone -, but not by panobinostat treatment. Importantly, pirfenidone therapy lead also to significant downregulation of the cancer-associated gene BIRC5, but was not associated with induction of ER stress and apoptosis. Finally, pirfenidone did not greatly affect expression of HDAC proteins. We conclude that generation and apoptosis resistance of IPF fibroblasts are mediated due to enhanced activity of HDAC proteins, and panobinostat can present a novel therapeutic option (in addition to pirfenidone) for IPF.