Contributions of alveolar epithelial cell quality control to pulmonary fibrosis
Jeremy Katzen, Michael F. Beers
Jeremy Katzen, Michael F. Beers
Published September 1, 2020
Citation Information: J Clin Invest. 2020;130(10):5088-5099. https://doi.org/10.1172/JCI139519.
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Contributions of alveolar epithelial cell quality control to pulmonary fibrosis

Abstract

Epithelial cell dysfunction has emerged as a central component of the pathophysiology of diffuse parenchymal diseases including idiopathic pulmonary fibrosis (IPF). Alveolar type 2 (AT2) cells represent a metabolically active lung cell population important for surfactant biosynthesis and alveolar homeostasis. AT2 cells and other distal lung epithelia, like all eukaryotic cells, contain an elegant quality control network to respond to intrinsic metabolic and biosynthetic challenges imparted by mutant protein conformers, dysfunctional subcellular organelles, and dysregulated telomeres. Failed AT2 quality control components (the ubiquitin-proteasome system, unfolded protein response, macroautophagy, mitophagy, and telomere maintenance) result in diverse cellular endophenotypes and molecular signatures including ER stress, defective autophagy, mitochondrial dysfunction, apoptosis, inflammatory cell recruitment, profibrotic signaling, and altered progenitor function that ultimately converge to drive downstream fibrotic remodeling in the IPF lung. As this complex network becomes increasingly better understood, opportunities will emerge to identify targets and therapeutic strategies for IPF.

Authors

Jeremy Katzen, Michael F. Beers

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Figure 3

Cell quality control dysfunction and resulting endophenotypes that contribute to fibrotic remodeling.

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Cell quality control dysfunction and resulting endophenotypes that contr...
AT2 cell quality control defects: Effective AT2 cell quality control relies on management of malformed or misfolded proteins (proteostasis), degradation of dysfunctional organelles, and maintenance of telomere length. AT2 response: The loss of quality control involves AT2 cell adaptive compensations, such as activation of the UPR/UPS to regain proteostasis. However, sustained quality control defects lead to cellular disruption and injury from ER stress, persistent mitochondrial dysfunction, metabolic reprograming, and DNA damage responses. AT2 endophenotypes: Modeling AT2 cell quality control defects and interrogation of the IPF epithelia have identified a number of AT2 cell endophenotypes in the fibrotic lung. These include the production of profibrotic mediators including TGF-β, loss of AT2 cells through apoptosis, challenges to progenitor cell function resulting in the loss of progenitor capacity from senescence or emergence of hyperproliferative AT2 cells, and recruitment of immune cell populations. Common IPF phenotype: The resultant loss of alveolar architecture in IPF is defined by fibrotic remodeling and myofibroblast expansion into fibroblastic foci and hyperplasia of lung epithelial cells.