LSC - 2017 - Hippo-YAP/TAZ signaling is deranged in IPF

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Abstract

Objective: Idiopathic pulmonary fibrosis (IPF) is a devastating disease with no cure and is characterized by deranged epithelial repair, myofibroblast activation, and excess deposition of extracellular matrix. Yes associated protein (YAP) and transcriptional co-regulator with PDZ-binding domain(TAZ), co-transcriptional activators of the Hippo pathway and proto-oncogenes, were recently found to be deranged in IPF. The cause of their dysregulation remain unknown. Hippo signaling regulates several endogenous progenitor cell functions through YAP/TAZ. We hypothesized that Hippo signaling is downregulated in IPF, resulting in increased YAP/TAZ activity.

Methods and Results: We assessed normal and fibrotic (IPF or intratracheal bleomycin-treated murine) lung tissue using immunohistochemistry, qPCR, and Gene Set Enrichment Analysis to identify cell types with deranged YAP/TAZ. Distal epithelial cells and fibroblasts were found to have dysregulated YAP/TAZ activity. Hippo components were downregulated in IPF and fibrotic mice, including in murine alveolar type II cells (mATII). Secretion of YAP/TAZ targets with pro-fibrotic activity was increased in fibrotic mATII as detected by mass spectrometry proteomics. Principal component analysis using Hippo expression in the Lung Gene Research Consortium separated IPF from normal patients. Fibrotic markers, including YAP/TAZ targets and myofibroblast activation, were reduced in the bleomycin model of fibrosis and in a novel ex vivo model of early pulmonary fibrosis in human precision cut lung slices when verteporfin, an FDA approved drug and YAP/TAZ inhibitor, was used therapeutically.

Conclusion: Hippo-YAP/TAZ are deranged in IPF. Pharmaceutical targeting of YAP/TAZ and or restoration of Hippo signaling may represent a new therapeutic strategy for IPF.

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  • Cell and Molecular Biology
Original languageEnglish
Article numberOA475
JournalEuropean Respiratory Journal
Volume50
Issue numberSuppl. 61
Publication statusPublished - 2017 Sep 6
Publication categoryResearch
Peer-reviewedYes