Robert L. Mayock & David A. Cooper Professor of Medicine
Department of Medicine, Pulmonary and Critical Care Division, Perelman School of Medicine, University of Pennsylvania , USA
Epithelial Cell Dysfunction In Lung Fibrosis: It’s About Proteostasis and Quality Control
Host: L. Braga
Idiopathic Pulmonary fibrosis (IPF) is a devastating interstitial lung disease (ILD) of older adults characterized by disruption of distal lung architecture that ultimately leads to scar formation, abnormal gas exchange, and respiratory failure. The identification of rare IPF associated genetic variants has provided valuable insight into cells and pathways that participate in fibrotic lung remodeling as part of a paradigm shift in which dysfunctional AT2 cells serve as a proximal driver of lung fibrosis. Coupled with the recent identification of a population of “reprogrammed” AT2 cells in human IPF lungs deficient in classic AT2 transcriptional programs and enriched in profibrotic mediators, new opportunities are emerging for therapeutic discovery for IPF. In this seminar we will explore the biology of the alveolar epithelial type 2 (AT2) cell-restricted Surfactant Protein C (SP-C) protein and discuss the use of known IPF- associated SP-C gene (SFTPC) variants and their aberrant proprotein isoforms as substrates in preclinical models to probe how the functional disruption in epithelial cell proteostasis and cell quality control (QC) participate in aberrant lung injury / repair. We will review the AT2 cell response to mutant SFTPC (unfolded protein response signaling, ubiquitin-proteasome degradation, disrupted macroautophagy, and ER stress) as well as recently published in vivo proof of concept studies showing disrupted AT2 QC can promote epithelial cell reprogramming and fibrotic remodeling. The data will be discussed in terms of underrepresented pathways of IPF pathogenesis and the added equipoise for using an array of experimental platforms to catalyze discovery and testing of new IPF therapies.
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