Contributions of alveolar epithelial cell quality control to pulmonary fibrosis
Jeremy Katzen, Michael F. Beers
Jeremy Katzen, Michael F. Beers
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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 1

IPF pathogenesis driven by epithelial dysfunction occurs in three phases.

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IPF pathogenesis driven by epithelial dysfunction occurs in three phases...
Initiation: Intrinsic (e.g., genetic) and extrinsic (e.g., infection, air pollution) factors acting through various pathways converge to produce a vulnerable alveolar type 2 epithelial cell (AT2) population (blue rectangular cells). Vulnerable AT2s subjected to continued intrinsic proteostatic/cell quality control challenges or additional secondary injurious stimuli (often recurrent) develop profound functional defects marked by aberrant activation of developmental programs, enhanced cell stress responses, impaired progenitor function, and/or apoptosis. Amplification: Dysfunctional AT2 cells (red rectangular cells) can initiate crosstalk with immune populations such as Ly6Chi monocytes, alveolar macrophages, neutrophils, or lymphocytes, which can both amplify the initial injury events and promote mesenchymal expansion further complemented by commensurate AT2/mesenchymal crosstalk. Fibrogenesis: The dysfunctional alveolar niche exhibits further feed-forward mechanisms to promote ongoing AT2 dysfunction marked by increased proliferation (AT2 hyperplasia), impaired transdifferentiation to AT1 cells, and upregulation of senescence programs. Coupled with enhanced myofibroblast activation and matrix deposition, the disrupted injury/repair response leads to scar formation and progressive loss of lung architectural complexity culminating in progressive fibrotic remodeling, physiological derangements in gas exchange, and a clinically evident IPF phenotype.