Cellular senescence in asthma: from pathogenesis to therapeutic challenges

Abstract

Asthma is a heterogeneous chronic respiratory disease that impacts nearly 10% of the population worldwide. While cellular senescence is a normal physiological process, the accumulation of senescent cells is considered a trigger that transforms physiology into the pathophysiology of a tissue/organ. Recent advances have suggested the significance of cellular senescence in asthma. With this review, we focus on the literature regarding the physiology and pathophysiology of cellular senescence and cellular stress responses that link the triggers of asthma to cellular senescence, including telomere shortening, DNA damage, oncogene activation, oxidative-related senescence, and senescence-associated secretory phenotype (SASP). The association of cellular senescence to asthma phenotypes, airway inflammation and remodeling, was also reviewed. Importantly, several approaches targeting cellular senescence, such as senolytics and senomorphics, have emerged as promising strategies for asthma treatment. Therefore, cellular senescence might represent a mechanism in asthma, and the senescence-related molecules and pathways could be targeted for therapeutic benefit.

Keywords: Asthma; Cellular senescence; SASP; Senolytics; Senomorphics.

Fig. 1

Physiology and pathophysiology of cellular senescence. Senescence is a normal process during aging and embryo development as a physiological state (Spring green). It plays a critical role in disease prevention or recovery by recruiting immune cells to maintain tissue homeostasis, initiate tissue repair and remodeling, and limit tumor progression (Deep sky blue). Senescence can also contributes to generate pro-inflammatory microenvironment, supporting tumor development, and promote chronic inflammation during aging and multiple age-related disease (Light salmon).

Fig. 2

Diverse exogenous and endogenous stresses trigger cellular senescence Hallmarks of cellular stress responses that link the triggers of asthma exogenous to the cellular senescence. These hallmarks include telomere shortening, DNA damage, oncogene activation, and oxidative related senescence that lead to enlarged cell morphology with a group of changes including senescence associated β-galactosidase (SA-β-gal) activation, cell cycle arrest (e.g., p16, p21), and release of SASP components.

Fig. 3

Overview of the major features of asthma. Asthma is divided into two endotype: eosinophilic (Th2-high) and neutrophilic (Th2-low). Th2-high asthma is mainly related to Th2 lymphocytes and M2-polarized macrophages that can enhance eosinophilic inflammation via releasing inflammatory cytokines (e.g., IL-4, IL-5, IL-13, and TGF-β). Th2-low asthma is related to Th1, Th17 lymphocytes, and M1 macrophages that can release Th1, Th17, and M1 macrophage-related cytokines (IFN-γ, IL-17, and IL-1β/IL-6/IL-8), further promoting the neutrophilic inflammation. Asthma is also characterized by structural changes (remodeling), including epithelial damage, subepithelial fibrosis, and increased smooth muscle mass. Stressors (DAMPs, pollutants, allergens) can induce airway epithelial cells to release cytokines like TSLP, IL-25, and IL-33, promoting airway remodeling and inflammation.