Abstract
Pulmonary senescence is accelerated by unresolved DNA damage response, underpinning susceptibility to pulmonary fibrosis. Recently it was reported that the SARS-Cov-2 viral infection induces acute pulmonary epithelial senescence followed by fibrosis, although the mechanism remains unclear. Here, we examine roles of alveolar epithelial stem cell senescence and senescence-associated differentiation disorders in pulmonary fibrosis, exploring the mechanisms mediating and preventing pulmonary fibrogenic crisis. Notably, the TGF-β signalling pathway mediates alveolar epithelial stem cell senescence by mechanisms involving suppression of the telomerase reverse transcriptase gene in pulmonary fibrosis. Alternatively, telomere uncapping caused by stress-induced telomeric shelterin protein TPP1 degradation mediates DNA damage response, pulmonary senescence and fibrosis. However, targeted intervention of cellular senescence disrupts pulmonary remodelling and fibrosis by clearing senescent cells using senolytics or preventing senescence using telomere dysfunction inhibitor (TELODIN). Studies indicate that the development of senescence-associated differentiation disorders is reprogrammable and reversible by inhibiting stem cell replicative senescence in pulmonary fibrosis, providing a framework for targeted intervention of the molecular mechanisms of alveolar stem cell senescence and pulmonary fibrosis. Abbreviations: DPS, developmental programmed senescence; IPF, idiopathic pulmonary fibrosis; OIS, oncogene-induced replicative senescence; SADD, senescence-associated differentiation disorder; SALI, senescence-associated low-grade inflammation; SIPS, stress-induced premature senescence; TERC, telomerase RNA component; TERT, telomerase reverse transcriptase; TIFs, telomere dysfunction-induced foci; TIS, therapy-induced senescence; VIS, virus-induced senescence.
Highlights
These findings indicate a primary mechanism through which environmental stress induces AEC1 cell damage and coerces AEC2 stem cells to succumb to replicative senescence and senescence-associated differentiation disorder (SADD) in pulmonary fibrosis
Consistent with stress-mediated TPP1 degradation, thereby telomere shortening and pulmonary fibrosis, we found that under-expression of TPP1 is sufficient to induce pulmonary senescence and fibrosis, indicating that TPP1 polyubiquitination at multiple sites triggered by stress incurs telomere uncapping, DDR and shortening, resulting in pulmonary senescence and fibrosis [35]
The senolytic targeting of virus-induced senescence (VIS) as a novel regimen option against COVID-19 indicates that cellular replicative senescence is causative to severe stress-induced acute SADD, tissue fibrogenic remodelling, and phenotypic onset, and that eliminating cellular replicative senescence is beneficial in managing pulmonary fibrosis
Summary
The mechanism of the accelerated cellular replicative senescence remains to be elucidated in association with widespread alveolar epithelial interstitial damages, epithelial cell repair failure, myofibroblast fibrogenic proliferation and extracellular matrix deposition [3–5]. In contrast to OIS, SIPS and VIS occur with excessive damages to serve as a proliferative and differentiative checkpoint to prevent cellular damage from passing onto daughter cells [3,34,35] It remains unclear how the cell cycle arrest is . Cells 2022, 11, 877 damages to serve as a proliferative and differentiative checkpoint to prevent cellular damage from passing onto daughter cells [3,34,35] It remains unclear how the cell cycle arrest is regulated in SIPS, OIS and VIS.
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