Inhibition of epithelial cell YAP-TEAD/LOX signaling attenuates pulmonary fibrosis in preclinical models
Abstract
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.
Article Details
Authors (34)
Darcy Elizabeth Wagner
Hani N. Alsafadi
Nilay Mitash
Aurelien Justet
Qianjiang Hu
Ricardo Pineda
Claudia Staab-Weijnitz
Martina Korfei
Nika Gvazava
Kristin Wannemo
Ugochi Onwuka
Molly Mozurak
Adriana Estrada-Bernal
Juan Cala-Garcia
Katrin Mutze
Rita Costa
Deniz Bölükbas
John Stegmayr
Wioletta Skronska-Wasek
Stephan Klee
Chiharu Ota
Hoeke A. Baarsma
Jingtao Wang
State Key Laboratory of Critical Metals Beneficiation, Metallurgy and Purification, School of Chemical Engineering
John Sembrat
Anne Hilgendorff
Jun Ding
Andreas Günther
Rachel Chambers
Ivan Rosas
Stijn De Langhe
Naftali Kaminski
Pulmonary, Critical Care, and Sleep Medicine, Yale School of Medicine, New Haven, CT
Mareike Lehmann
Oliver Eickelberg
Melanie Königshoff