Cellular Senescence Drives Chronic Obstructive Pulmonary Disease
Researchers here review the evidence for accumulating numbers of senescent cells to drive the dysfunction of chronic obstructive pulmonary disease (COPD). It is now well known that senescent cells secrete a potent mix of signals that provoke inflammation and remodeling of tissue structure. This is necessary in the short term as a response to injury, potentially cancerous cells, and similar issues that require the attention of the immune system, regeneration, and potentially the destruction of errant cells. When sustained for the long term, however, it is highly disruptive to tissue structure and function, producing outcomes such as fibrosis and a chronic, unresolved inflammation that harmfully alters cell behavior.
Researchers coined the term "COPD-associated secretory phenotype" (CASP) to refer to the inflammatory mediators that are increased in COPD and provided a comparison of CASP and senescence-associated secretory phenotype (SASP) factors. In summary, there is a large degree of overlap, supporting the notion that they are strongly linked and reinforces the theory that senescence, along with SASP, is a major contributor to the inflammation that defines COPD.
Typically, cells undergoing senescence chemoattract immune cells, resulting in clearance of these senescent cells by immune cells such as NK cells and macrophages. However, senescent cells in diseased tissues can also impede innate and adaptive immune responses. Senescent cells accumulate in tissues during aging and could influence several pathological features observed in COPD, such as inflammation-associated tissue damage and remodeling. It is difficult to determine whether inflammation observed in COPD is primarily due to senescence, as many other contributing factors within the disease may contribute. However, the presence of enhanced senescent cell frequency in the lungs does contribute to a modified immune response that may influence several aspects of COPD pathogenesis.
There is increasing interest in the resolution of abundant senescence as a potential therapeutic approach in COPD. Senolytic agents, compounds that facilitate the elimination of senescent cells, have received considerable attention lately as a potential treatment for COPD. However, the investigation of these agents is limited by the lack of universal markers of senescence. A better understanding of pathways that induce and reinforce senescence in COPD may allow us to discover possible biomarkers that could serve as targets for these senolytic therapies.
Overall, there is mounting evidence to suggest that senescence could contribute to cells being resistant to apoptosis, exhibiting elevated inflammation, and reduced dead cell clearance, resulting in extensive tissue remodeling observed in COPD. Targeting senescent cells using senolytics to selectively remove senescent cells or modulate SASP using small molecules or antibodies represents a novel approach to countering COPD progression. Several treatments that may target cellular senescence are in development.