Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models
Darcy E. Wagner, Hani N. Alsafadi, Nilay Mitash, A. Justet, Qianjiang Hu, Ricardo Pineda, Claudia A. Staab-Weijnitz, Martina Korfei, Nika Gvazava, Kristin Wannemo, Ugochi Onwuka, Molly Mozurak, Adriana Estrada‐Bernal, Juan Cala-García, Kathrin Mutze, Rita Costa, Deniz A. Bölükbas, John Stegmayr, Wioletta Skrońska-Wąsek, Stephan Klee, Chiharu Ota, Hoeke A. Baarsma, Jingtao Wang, John Sembrat, Anne Hilgendorff, Jun Ding, Andreas Günther, Rachel C. Chambers, Iván O. Rosas, Stijn De Langhe, Naftali Kaminski, Mareike Lehmann, Oliver Eickelberg, Mélanie Königshoff
Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal disease characterized by excessive extracellular matrix deposition. Current IPF therapies slow disease progression but do not stop or reverse it. The (myo)fibroblasts are thought to be the main cellular contributors to excessive extracellular matrix production in IPF. Here we show that fibrotic alveolar type II cells regulate production and crosslinking of extracellular matrix via the co-transcriptional activator YAP. YAP leads to increased expression of Lysl oxidase (LOX) and subsequent LOX-mediated crosslinking by fibrotic alveolar type II cells. Pharmacological YAP inhibition via verteporfin reverses fibrotic alveolar type II cell reprogramming and LOX expression in experimental lung fibrosis in vivo and in human fibrotic tissue ex vivo. We thus identify YAP-TEAD/LOX inhibition in alveolar type II cells as a promising potential therapy for IPF patients.