![]() Mutations affecting AT2 cell functions ( ABCA3, SFTPA, SFTPB, and SFTPC) are among the genetic causes of chronic ILDs, further implicating abnormal alveolar epithelial cell homeostasis in the pathogenesis of these disorders ( 8– 11). Genome-wide transcriptomic analyses of lung tissue and isolated epithelial cells from IPF patients demonstrate dramatic changes in ciliated, basal, and goblet cell–associated gene expression and loss of normal alveolar epithelial cells, reflecting profound changes in epithelial cell differentiation and function in IPF ( 6, 7). Fibrotic lesions and honeycomb structures replace alveolar structures, the latter normally lined by AT1 and AT2 cells. Histologically, respiratory epithelial cells in the lung parenchyma express atypical proximal airway epithelial and indeterminate cell type markers ( 5, 6), including goblet and basal cell characteristics that are normally restricted to conducting airways. Though the underlying causes of the disease remain elusive, genetic and experimental evidence support the concept that chronic alveolar injury and failure to properly repair the respiratory epithelium are intrinsic to IPF disease pathogenesis ( 4). IPF pathogenesis encompasses fibrotic remodeling, inflammation, and loss of lung architecture ( 3). Idiopathic pulmonary fibrosis (IPF) is a common form of interstitial lung disease (ILD) resulting in alveolar remodeling and progressive loss of pulmonary function, respiratory failure, and death often within 5 years of diagnosis ( 1, 2). YAP and mTOR/p-S6 signaling pathways interact to induce cell proliferation and migration, and inhibit epithelial cell differentiation that may contribute to the pathogenesis of IPF. Activation of p-S6 was required for enhancing and stabilizing YAP, and the p-S6 inhibitor temsirolimus blocked nuclear YAP localization and suppressed expression of YAP target genes CTGF, AXL, and AJUBA ( JUB). Expression of YAP (S127A), a constitutively active form of YAP, in human bronchial epithelial cells (HBEC3s) increased p-S6 and p-PI3K, cell proliferation and migration, processes that were inhibited by the YAP-TEAD inhibitor verteporfin. Phospho-S6 (p-S6) and p-PTEN were increased in IPF epithelial cells, consistent with activation of mTOR signaling. Bioinformatic analyses of epithelial cell RNA profiles predicted increased activity of YAP and increased canonical mTOR/PI3K/AKT signaling in IPF. ![]() Immunofluorescence staining in IPF epithelial cells demonstrated increased nuclear YAP and loss of MST1/2. Herein we demonstrate increased YAP activity in respiratory epithelial cells in lungs of patients with idiopathic pulmonary fibrosis (IPF), a common, lethal form of interstitial lung disease (ILD). ![]() Hippo/YAP signaling plays pleiotropic roles in the regulation of cell proliferation and differentiation during organogenesis and tissue repair. ![]()
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