Airway Epithelium Senescence as a Driving Mechanism in COPD Pathogenesis

Abstract

Cellular senescence is a state of permanent cell cycle arrest triggered by various intrinsic and extrinsic stressors. Cellular senescence results in impaired tissue repair and remodeling, loss of physiological integrity, organ dysfunction, and changes in the secretome. The systemic accumulation of senescence cells has been observed in many age-related diseases. Likewise, cellular senescence has been implicated as a risk factor and driving mechanism in chronic obstructive pulmonary disease (COPD) pathogenesis. Airway epithelium exhibits hallmark features of senescence in COPD including activation of the p53/p21WAF1/CIP1 and p16INK4A/RB pathways, leading to cell cycle arrest. Airway epithelial senescent cells secrete an array of inflammatory mediators, the so-called senescence-associated secretory phenotype (SASP), leading to a persistent low-grade chronic inflammation in COPD. SASP further promotes senescence in an autocrine and paracrine manner, potentially contributing to the onset and progression of COPD. In addition, cellular senescence in COPD airway epithelium is associated with telomere dysfunction, DNA damage, and oxidative stress. This review discusses the potential mechanisms of airway epithelial cell senescence in COPD, the impact of cellular senescence on the development and severity of the disease, and highlights potential targets for modulating cellular senescence in airway epithelium as a potential therapeutic approach in COPD.

Keywords: COPD; SASP; airway epithelial cells; cellular senescence; pathogenesis.

Figure 1

Mechanisms of airway epithelium senescence in COPD and potential therapeutic targets. Created using BioRender.com. Red boxes and solid lines represent senescence inducers and senescence signaling pathways. Light and darker green boxes and dotted lines represent potential therapeutic approches and drugs targeting senescence.

Figure 2

Possible mechanisms of SASP regulation on COPD airway epithelium. Created using BioRender.com. Red and dark red boxes represent key inducers that mediate the secretions of SASP through differenct signal pathways in an autocrine manner. Green writings and box represent mediators that are involed in spreading senesence to neighbouring cells in a paracrine manner.