The aged extracellular matrix and the profibrotic role of senescence-associated secretory phenotype

Abstract

Idiopathic pulmonary fibrosis (IPF) is an irreversible and fatal lung disease that is primarily found in the elderly population, and several studies have demonstrated that aging is the major risk factor for IPF. IPF is characterized by the presence of apoptosis-resistant, senescent fibroblasts that generate an excessively stiff extracellular matrix (ECM). The ECM profoundly affects cellular functions and tissue homeostasis, and an aberrant ECM is closely associated with the development of lung fibrosis. Aging progressively alters ECM components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction through the expression of factors linked to a senescence-associated secretary phenotype (SASP). There is growing evidence that SASP factors affect various cell behaviors and influence ECM turnover in lung tissue through autocrine and/or paracrine signaling mechanisms. Since life expectancy is increasing worldwide, it is important to elucidate how aging affects ECM dynamics and turnover via SASP and thereby promotes lung fibrosis. In this review, we will focus on the molecular properties of SASP and its regulatory mechanisms. Furthermore, the pathophysiological process of ECM remodeling by SASP factors and the influence of an altered ECM from aged lungs on the development of lung fibrosis will be highlighted. Finally, recent attempts to target ECM alteration and senescent cells to modulate fibrosis will be introduced.NEW & NOTEWORTHY Aging is the most prominent nonmodifiable risk factor for various human diseases including Idiopathic pulmonary fibrosis. Aging progressively alters extracellular matrix components and is associated with the accumulation of senescent cells that promote age-related tissue dysfunction. In this review, we will discuss the pathological impact of aging and senescence on lung fibrosis via senescence-associated secretary phenotype factors and potential therapeutic approaches to limit the progression of lung fibrosis.

Keywords: ECM; EVs; IPF; SASP: senescence; aging.

Graphical abstract

Figure 1.

Cellular interplay via senescence-associated secretory phenotype (SASP) factors and lung fibrosis. Senescent cells express SASP factors including senescence-associated extracellular vesicles (EVs). EVs generated by different cells can exert their effects on a number of different target cells, highlighting the contextual nature of intercellular communication mediated by EVs. EVs contain different surface molecules such as proteins and carbohydrates that allow them to target receptor cells and interact with the extracellular matrix (ECM), which affects the physiochemical properties and function of ECM (87). Altered ECM also affects cellular properties by direct interaction with cells or activates several SASP factors, propagating the fibrotic process. The ability of EVs to diffuse through a complex and stiff ECM can be influenced by various factors, including the size, shape, and surface properties of the EVs, as well as the properties of the ECM. Created with BioRender.com.