Cellular Senescence: Pathogenic Mechanisms in Lung Fibrosis

Abstract

Pulmonary fibrosis is a chronic and fatal lung disease that significantly impacts the aging population globally. To date, anti-fibrotic, immunosuppressive, and other adjunct therapy demonstrate limited efficacies. Advancing our understanding of the pathogenic mechanisms of lung fibrosis will provide a future path for the cure. Cellular senescence has gained substantial interest in recent decades due to the increased incidence of fibroproliferative lung diseases in the older age group. Furthermore, the pathologic state of cellular senescence that includes maladaptive tissue repair, decreased regeneration, and chronic inflammation resembles key features of progressive lung fibrosis. This review describes regulatory pathways of cellular senescence and discusses the current knowledge on the senescence of critical cellular players of lung fibrosis, including epithelial cells (alveolar type 2 cells, basal cells, etc.), fibroblasts, and immune cells, their phenotypic changes, and the cellular and molecular mechanisms by which these cells contribute to the pathogenesis of pulmonary fibrosis. A few challenges in the field include establishing appropriate in vivo experimental models and identifying senescence-targeted signaling molecules and specific therapies to target senescent cells, known collectively as “senolytic” or “senotherapeutic” agents.

Endothelial Senescence and the Chronic Vascular Diseases: Challenges and Therapeutic Opportunities in Atherosclerosis

“…In vivo senescent endothelial cells of animal models and human tissues have been identified in different pathological conditions [25]. For example, senescence-associated beta-galactosidase (SA-β-gal) dye [26] is a commonly used marker to recognize cellular senescence, and it has revealed an increase of senescent endothelial cells in diabetic Zucker rats [27,28].…”

Differential LysoTracker Uptake Defines Two Populations of Distal Epithelial Cells in Idiopathic Pulmonary Fibrosis

“…Although new therapies significantly increased the duration and quality of life of IPF patients, a therapeutic regimen that can arrest or, even better, reverse disease progression remains to be discovered [ 4 ]. Partly responsible for this situation is our limited understanding of the cellular states and processes that each of the more than 40 cell types in the lung undergoes, in an active (causative) or reactive manner in homeostatic and injury contexts [ 5 , 6 ]. A number of recent studies clearly identified the chronic injury of the alveolar type 2 epithelial cells (AEC2s) as the initial site of injury in the IPF lung [ 7 , 8 , 9 ].…”

COVID-19 lung disease shares driver AT2 cytopathic features with Idiopathic pulmonary fibrosis

“…Our PPI network analyses suggested that AT2 senescence and progenitor arrested state in the setting of a ViP/sViP-immune response (cytokine storm contributed by PBMCs) may support a SASP phenotype, which is a pathological feature of aging and IPF lung. 97 , 98 …”