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. IPF pathogenesis encompasses fibrotic remodeling, inflammation, and loss of lung architecture. Although 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. Histologically, respiratory epithelial cells in the lung parenchyma express atypical proximal airway epithelial and indeterminate cell type markers, including goblet and basal cell (BC) characteristics that are normally restricted to conducting airways. Fibrotic lesions and honeycomb structures replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. 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. One strategy to attenuate or reverse the manifestations of IPF is to trigger proper alveolar regeneration by endogenous lung stem cells. Changes in cell density and matrix stiffness as a result of injury are sensed by the Hippo pathway, which controls stem cell quiescence. Recent reports also indicate increased YAP activity in respiratory epithelial cells in lungs of patients with IPF. Individual IPF epithelial cells that feature aberrant YAP activation in bronchiolized honeycomb regions frequently co-expressed AT1, AT2, conducting airway selective markers and even mesenchymal or EMT markers, demonstrating indeterminate states of differentiation not seen in normal lung development. Our preliminary findings indicate that inactivation of the Hippo pathway impairs alveolar epithelial regeneration, whereas inactivation of Yap promotes the resolution of pulmonary fibrosis. Using the new techniques and tools we have generated we will define the molecular pathways and mechanism by which the Hippo pathway controls alveolar epithelial regeneration after bleomycin injury.
Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive, and ultimately fatal disorder with a poorly understood pathogenesis and no cure. IPF lungs feature honeycomb regions, which are lined with confused conducting airway epithelial cells stuck in an indeterminate state of differentiation. This grant proposal seeks to determine the role of Hippo signaling in regulating alveolar epithelial regeneration by bronchial and alveolar epithelial stem cells after bleomycin injury.