Senescence of Alveolar Epithelial Progenitor Cells: A Critical Driver of Lung Fibrosis.
American journal of physiology. Cell physiology(2023)
Abstract
Pulmonary fibrosis comprises a range of chronic interstitial lung diseases (ILD) that significantly burden patients and public health. Among these, idiopathic pulmonary fibrosis (IPF), a disease of aging, is the most common and most severe form of ILD and is treated largely by lung transplantation. The lack of effective treatments to stop or reverse lung fibrosis - in fact, fibrosis in most organs - has sparked the need to understand causative mechanisms with the goal of identifying critical points for potential therapeutic intervention. Findings from many groups have indicated that repeated injury to the alveolar epithelium - where gas exchange occurs - leads to stem cell exhaustion and impaired alveolar repair that, in turn, triggers in the onset and progression of fibrosis. Cellular senescence of alveolar epithelial progenitors is a critical cause of stemness failure. Hence, senescence impairs repair and thus contributes significantly to fibrosis. In this review, we discuss recent evidence indicating that senescence of epithelial progenitor cells impairs alveolar homeostasis and repair, creating a profibrotic environment. Moreover, we discuss the impact of senescence alveolar epithelial progenitors, alveolar type 2 (AT2) cells, and AT2-derived transitional epithelial cells in fibrosis. Emerging evidence indicates that transitional epithelial cells are prone to senescence and, hence, are a new player involved in senescence-associated lung fibrosis. Understanding the complex interplay of cell types and cellular regulatory factors contributing to alveolar epithelial progenitor senescence will be crucial to developing targeted therapies to mitigate their downstream profibrotic sequelae and to promote normal alveolar repair.
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Key words
epithelial cells, fibrosis, progenitor cells, SASP, senescence
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