Cellular Senescence: A Troy Horse in Pulmonary Fibrosis

Abstract

Pulmonary fibrosis (PF) is a chronic interstitial lung disease characterized by myofibroblast abnormal activation and extracellular matrix deposition. However, the pathogenesis of PF remains unclear, and treatment options are limited. Epidemiological studies have shown that the average age of PF patients is estimated to be over 65 years, and the incidence of the disease increases with age. Therefore, PF is considered an age-related disease. A preliminary study on PF patients demonstrated that the combination therapy of the anti-senescence drugs dasatinib and quercetin improved physical functional indicators. Given the global aging population and the role of cellular senescence in tissue and organ aging, understanding the impact of cellular senescence on PF is of growing interest. This article systematically summarizes the causes and signaling pathways of cellular senescence in PF. It also objectively analyzes the impact of senescence in AECs and fibroblasts on PF development. Furthermore, potential intervention methods targeting cellular senescence in PF treatment are discussed. This review not only provides a strong theoretical foundation for understanding and manipulating cellular senescence, developing new therapies to improve age-related diseases, and extending a healthy lifespan but also offers hope for reversing the toxicity caused by the massive accumulation of senescence cells in humans.

NR2F2 alleviates pulmonary fibrosis by inhibition of epithelial cell senescence

“…Despite the FDA approval of two drugs, pirfenidone and nintedanib, for the treatment of IPF, these medications only moderately slow disease progression and are associated with certain adverse reactions [6,28]. Given the global aging population and cell senescence as a major driving force for tissue and organ aging, there is an urgent need to identify new targets for regulating cellular senescence [29]. In this study, we found that NR2F2 was downregulated in the lung tissue of both IPF patients and bleomycin-induced fibrotic mouse models.…”

“…Multiple studies have found a widespread presence of SASP in various senescent cell populations in the lungs of experimental pulmonary fibrosis models and IPF patients [40][41][42]. These SASP components not only serve as markers of senescence in the lung fibrosis development process but also actively participate in the senescence process and regulate the progression of pulmonary fibrosis [29]. Therefore, we further investigated whether senescent epithelial cells regulated by NR2F2 would express and secrete excessive SASP factors, thereby influencing the activation of lung fibroblasts through paracrine effects.…”

“…Studies have found that during the occurrence and development of pulmonary fibrosis, various factors can induce cell senescence, such as oxidative stress, telomere attrition, oncogene activation, and ionizing radiation. In addition, DNA damage is also an inducer of cell senescence [29,47]. The pathogenesis of pulmonary fibrosis induced by environmental factors and genetic toxic substances to some extent leads to DNA damage [48].…”

Molecular mechanisms of aging and anti-aging strategies

“…Senescent cells secrete a number of cytokines, including proinflammatory cytokine and chemokines, growth regulators, angiogenic factors and matrix metalloproteinase, collectively known as the SASP or the senescence information secretory group. SASP has been recognized as a marker of senescent cells and mediates many pathophysiological effects [198]. In addition, DNA damage, telomere depletion, epigenetic changes, protein damage, lipid damage, dysfunction of mitochondria and lysosomes, ROS and inflammation are all important inducers of cell senescence [199].…”

“…Senescent cells exhibit abnormally high levels of damage accumulation, including DNA damage, telomere dysfunction, mitochondrial dysfunction and ROS accumulation [201]. Elimination of senescent cells reduces the number of cells with the highest degree of damage [191,198]. Therefore, treatment methods that improve or delay cellular senescence characteristics are important strategies for delaying aging.…”