Cellular Senescence in Lung Fibrosis

Abstract

Fibrosing interstitial lung diseases (ILDs) are chronic and ultimately fatal age-related lung diseases characterized by the progressive and irreversible accumulation of scar tissue in the lung parenchyma. Over the past years, significant progress has been made in our incomplete understanding of the pathobiology underlying fibrosing ILDs, in particular in relation to diverse age-related processes and cell perturbations that seem to lead to maladaptation to stress and susceptibility to lung fibrosis. Growing evidence suggests that a specific biological phenomenon known as cellular senescence plays an important role in the initiation and progression of pulmonary fibrosis. Cellular senescence is defined as a cell fate decision caused by the accumulation of unrepairable cellular damage and is characterized by an abundant pro-inflammatory and pro-fibrotic secretome. The senescence response has been widely recognized as a beneficial physiological mechanism during development and in tumour suppression. However, recent evidence strengthens the idea that it also drives degenerative processes such as lung fibrosis, most likely by promoting molecular and cellular changes in chronic fibrosing processes. Here, we review how cellular senescence may contribute to lung fibrosis pathobiology, and we highlight current and emerging therapeutic approaches to treat fibrosing ILDs by targeting cellular senescence.

Keywords: aging; pulmonary fibrosis; senescence; senolytics; senomorphics.

Figure 1

Pathogenesis and perpetuation of fibrosing interstitial lung diseases. Environmental risk factors, age-related cell perturbations, genetic predisposition, persistent exposure to antigens and autoimmune diseases are identified as important factors that increase susceptibility to epithelial lung injury acting as initial triggers of the disease. In an early phase, shown in the left part of the figure (1), epithelial type 2 cells (AEC2) show several markers of stress, activation, and senescence, as they fail to respond to stress resulting in an impaired capacity of the lung to regenerate. In a later phase, and especially after repeated alveolar damage, sustained aberrant activation and senescence of the epithelium (2) leads to the hyperactive secretion of high levels of pro-fibrotic growth factors, cytokines, chemokines and matrix metalloproteinases, collectively known as senescence-associated secretory phenotype (SASP) factors (3), that promote cellular senescence of the adjacent AEC2 (4). This initial event is encompassed in a process called primary senescence, which is thought to be characterized by the appearance of a senescent lung epithelium which persists by adapting its metabolic pathways and becoming resistant to apoptosis. In this later phase, a dysregulated crosstalk between the senescent epithelium and the mesenchymal cells through SASP factors will give rise to the accumulation of fibroblasts and myofibroblasts, resulting in an increased production and deposition of extracellular matrix components (5). A considerable part of fibroblasts and myofibroblasts will present a stressed and senescent phenotype, including resistance to apoptosis, which entails a process called secondary or paracrine senescence. As a consequence, in the context of senescence in lung injury and repair, the accumulation of extracellular matrix components in the interstitium of the lung will lead to lung fibrosis.