Reviewing the Role of Cellular Senescence in Pulmonary Fibrosis
The first small human clinical trial of the senolytic therapy of dasatinib and quercetin targeted idiopathic pulmonary fibrosis, showing some benefit to patients. Later trials for kidney disease demonstrated that this treatment does remove a fraction of lingering senescent cells in human tissues in much the same way as it does in mice. Senescent cells accumulate with age in tissues throughout the body, the burden of these cells resulting from a growing gap between pace of creation and pace of clearance by the immune system. Researchers are coming to see a prominent role for senescent cells in all fibrotic conditions, in which excess extracellular matrix is produced, disrupting tissue structure and function. Compelling evidence in animal studies demonstrates reversal of fibrosis following senolytic treatment, a goal that is presently hard to achieve for human patients using existing interventions, those presently widely available in the clinic.
Pulmonary fibrosis (PF) is a chronic, progressive, devastating, and irreversible interstitial lung disease, with a median survival of 2 to 3 years after diagnosis. The present comprehension of the pathogenesis of PF entails the repetitive injury of alveolar epithelial cells (AECs) due to various risk factors, such as environmental exposure, viral infections, genetic predisposition, oxidative stress, and immunological factors. This injury subsequently results in the abnormal activation of AECs and dysregulated epithelial repair processes. The dysregulated epithelial cell secretes multiple cytokines and growth factors and interacts with endothelial, mesenchymal, and immune cells via multiple signaling mechanisms to trigger fibroblast and myofibroblast activation and promote extracellular matrix deposition, ultimately leading to the destruction of lung function, diminished exercise tolerance, and a decreased quality of life.
The existing epidemiological data from various data sources indicate that the average age of patients with PF is estimated to be over 65 years, and the incidence increases with age. Furthermore, individuals aged 70 and above have a risk of developing PF that is seven times higher than those in their 40s. Therefore, PF is now considered an age-related lung disease. Among the hallmarks of aging, cellular senescence serves as the primary driver behind tissue and organ aging, as well as an independent risk factor for PF progression. Age-related disturbances were increasingly observed in epithelial cells and fibroblasts in PF lungs compared to age-matched cells in normal lungs. Physiologically, alveolar epithelial type II (ATII) cells, serving as progenitor cells of the alveoli, differentiate into alveolar type 1 (ATI) cells in response to injury. Utilizing organoid cultures, single-cell transcriptomics, and lineage tracing, it has been discovered that ATII cells differentiate into ATI cells and acquire a transitional state known as pre-alveolar type 1 cell during the process of maturation. This transitional state exhibits regulation by TP53 signaling, making it susceptible to DNA damage and undergoing transient senescence.
However, there are at least two harmful consequences of persistent senescence. On the one hand, telomere wear and mitochondrial dysfunction lead to permanent cell-cycle arrest, which in turn causes stem cell/progenitor cell-renewal dysfunction and the loss of self-repair and regeneration abilities. On the other hand, senescent cells produce pro-inflammatory, pro-fibrotic, and stroma-remodeling cytokines such as IL-6, TGF-β, and several matrix metalloproteinases collectively known as the senescence-associated secretory phenotype (SASP), which can activate myofibroblast and scar formation. In fact, some components of SASP appear to enhance the growth arrest of exposed adjacent cells in a paracrine manner, further driving senescence, leading to low-grade chronic inflammation, and increasing susceptibility to pulmonary fibrosis.
A comprehensive understanding of how senescence promotes the occurrence and progression of PF can provide new insights into the further treatment of age-related diseases. This review presents compelling recent evidence indicating that cellular senescence is a significant driving factor in age-related lung diseases such as PF. It systematically summarizes the causes of cellular senescence in PF and the signaling pathways regulating different types of cellular senescence and also provides potential therapeutic strategies for targeting cellular senescence to improve PF. These strategies include targeting the clearance of senescent cells, intervening in senescence-related signaling pathways, and inhibiting the secretion of SASP.