Cellular senescence in the lung across the age spectrum

Abstract

Cellular senescence results in cell cycle arrest with secretion of cytokines, chemokines, growth factors, and remodeling proteins (senescence-associated secretory phenotype; SASP) that have autocrine and paracrine effects on the tissue microenvironment. SASP can promote remodeling, inflammation, infectious susceptibility, angiogenesis, and proliferation, while hindering tissue repair and regeneration. While the role of senescence and the contributions of senescent cells are increasingly recognized in the context of aging and a variety of disease states, relatively less is known regarding the portfolio and influences of senescent cells in normal lung growth and aging per se or in the induction or progression of lung diseases across the age spectrum such as bronchopulmonary dysplasia, asthma, chronic obstructive pulmonary disease, or pulmonary fibrosis. In this review, we introduce concepts of cellular senescence, the mechanisms involved in the induction of senescence, and the SASP portfolio that are relevant to lung cells, presenting the potential contribution of senescent cells and SASP to inflammation, hypercontractility, and remodeling/fibrosis: aspects critical to a range of lung diseases. The potential to blunt lung disease by targeting senescent cells using a novel class of drugs (senolytics) is discussed. Potential areas for future research on cellular senescence in the lung are identified.

Potential Role of Cellular Senescence in Asthma

“…SASPs include inflammatory cytokines such as interleukin-6 (IL-6), interleukin-8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1), growth regulators such as GRO and insulin-like growth factor binding protein-2 (IGFBP-2), cell survival modulators such as OPG and sTNF RI, and shed surface proteins such as uPAR and ICAM-1. Although the SASP in senescent fibroblasts and epithelial cells are not totally the same (Coppé et al, 2008), they execute similar functions in lung diseases, such as promoting cellular senescence, wound repair, and airway remodeling (Parikh et al, 2019b).…”

“…Persistent accumulation of senescent cells during aging induces low-grade inflammation through SASP (Acosta et al, 2013), impairs the immune system (Savale et al, 2009;Albrecht et al, 2014), and increases the vulnerability and susceptibility of organs to various pathological challenges (López-Otín et al, 2013). In respiratory system, cellular senescence has established role in the pathogenesis of aging-related diseases like chronic obstructive pulmonary disease (COPD) and idiopathic pulmonary fibrosis (IPF) (Tsuji et al, 2006;Diaz de Leon et al, 2010;Kuwano et al, 2016;Álvarez et al, 2017;Yanagi et al, 2017;Rashid et al, 2018;Schuliga et al, 2018;Vij et al, 2018;Araya et al, 2019;Fang et al, 2019;Parikh et al, 2019b). However, little is known about the place of cellular senescence in the development of asthma.…”

“…Amassing data has showed that pulmonary cells of COPD and IPF exhibit a senescent phenotype, which is involved in promoting airway chronic inflammation, airway remodeling, and lung function decline (Tsuji et al, 2006;Yao et al, 2012;Álvarez et al, 2017;Yanagi et al, 2017;Rashid et al, 2018;Schuliga et al, 2018;Vij et al, 2018;Araya et al, 2019;Fang et al, 2019;Parikh et al, 2019b). Increased senescence-associated proteins p16 and p21 in alveolar cells are correlated with airflow limitation of patients with emphysema (Tsuji et al, 2006).…”

Senescence in the lung: is this getting old?

“…Senescent cells have been reported in both human and animal models of pulmonary diseases (1,4,19,21,24,25,34,42,47,59,61,63). What is less clear is the extent to which phenotypic changes associated with normal chronological aging or in disease states are mechanistically attributable to cellular senescence or effects of senescent cells per se, i.e., how important are senescent cells in pathophysiology?…”

“…Thus, it is likely that on the one hand, normal physiological processes throughout life and external insults induce senescence, while conversely, senescent cells (via SASP) can induce and promote normal growth and repair or induce and promote disease, overall creating a feed-forward system [as highlighted in a recent review on cellular senescence in the lung (42)]. Accordingly, it becomes important to understand the contributions of senescence to development, aging, and disease, and if significant, the processes that lead to enhanced senescent cell burden and downstream detrimental effects.…”