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Abstract
Cellular senescence is a key process in physiological dysfunction developing upon aging or following diverse stressors including ionizing radiation. It describes the state of a permanent cell cycle arrest, in which proliferating cells become resistant to growth-stimulating factors. Senescent cells differ from quiescent cells, which can re-enter the cell cycle and from finally differentiated cells: morphological and metabolic changes, restructuring of chromatin, changes in gene expressions and the appropriation of an inflammation-promoting phenotype, called the senescence-associated secretory phenotype (SASP), characterize cellular senescence. The biological role of senescence is complex, since both protective and harmful effects have been described for senescent cells. While initially described as a mechanism to avoid malignant transformation of damaged cells, senescence can even contribute to many age-related diseases, including cancer, tissue degeneration, and inflammatory diseases, particularly when senescent cells persist in damaged tissues. Due to overwhelming evidence about the important contribution of cellular senescence to the pathogenesis of different lung diseases, specific targeting of senescent cells or of pathology-promoting SASP factors has been suggested as a potential therapeutic approach. In this review, we summarize recent advances regarding the role of cellular (fibroblastic, endothelial, and epithelial) senescence in lung pathologies, with a focus on radiation-induced senescence. Among the different cells here, a central role of epithelial senescence is suggested.
Highlights
Cellular senescence and in particular the ‘cellular senescence phenotype’ was initially discovered by Leonard Hayflick in 1961, who observed that the number of cell divisions in fibroblasts was limited and these normal, non-transformed cells reached the end of their replicative life span upon prolonged culturing, because the telomeres had reached a critical length [1,2]
Cellular senescence is considered an important driving force for the development of chronic lung pathologies, chronic inflammation observed in lungs of aging patients and of patients suffering from asthma, chronic obstructive pulmonary diseaseor pulmonary fibrosis
Its inhibition with an antagomir in turn resulted in restored sirtuin-1/6 levels, a reversed cell cycle arrest and reduced senescence and respective senescence-associated secretory phenotype (SASP) in epithelial cells from the peripheral airways of patients with chronic obstructive pulmonary disease (COPD) [48]
Summary
Cellular senescence and in particular the ‘cellular senescence phenotype’ was initially discovered by Leonard Hayflick in 1961, who observed that the number of cell divisions in fibroblasts was limited and these normal, non-transformed cells reached the end of their replicative life span upon prolonged culturing, because the telomeres had reached a critical length [1,2]. Increased DNA damage and/or inefficient damage removal results in chronic DDR signaling that can foster apoptotic cell death or a stable cell cycle arrest—cellular senescence [5,6]. This senescence-associated cell cycle arrest (mostly G1) depends on the activation of the cyclin-dependent kinase (CDK) inhibitors p21/WAF1 and p16/INK4A, the decisive components of tumor-suppressor pathways that are governed by the p53 and retinoblastoma (Rb) proteins, respectively [7,8]. Upon secretion from senescent cells, these SASP factors usually act in a paracrine manner to stimulate proliferation and/or transformation of adjacent immortalized cells, or even might trigger the senescence of other cells in the microenvironment
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