Cellular Senescence in Idiopathic Pulmonary Fibrosis
This review paper goes into some detail regarding present thought on the role of senescent cells of different types in idiopathic pulmonary fibrosis. Fibrosis in general is an often age-related dysfunction of normal tissue maintenance and regeneration, in which excessive extracellular matrix is created, leading to scar-like deposits that disrupt normal tissue structure and function. In the lung, this progressively impairs breathing and is ultimately fatal. Idiopathic pulmonary fibrosis was one of the first conditions for which early senolytic drugs to clear senescent cells were tested in humans.
Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial lung disease of unknown origin. Histologically, IPF is characterized by massive accumulation of fibroblasts, myofibroblasts, alveolar epithelial cells (AECs), and macrophages and a significant deposition of extracellular matrix (ECM). A previous review showed that AECs, as the main source of pro-fibrogenic cytokines in IPF, express a variety of cytokines and growth factors, which can promote the migration, proliferation, and accumulation of extracellular matrix of fibroblasts; these are key events of cell dysfunction in PF.
AECs are damaged by pathogenic microorganisms, dust, drugs, chemicals, and oxygen free radicals which, when coupled with risk factors such as aging and genetics, may decrease the ability of alveolar epithelial type II (ATII) cells and lung fibroblasts (LFs) to repair damage to the lung. LFs proliferate locally, migrate to the injury site and differentiate into myofibroblasts, which produce a large amount of ECM and exhibit contractile function. These myofibroblasts typically vanish after successful repair; dysregulation of the normal repair process can lead to persistent myofibroblast activation.
PF is an aging-associated lung disease in which LF and AEC senescence play a complex role in pathogenesis. Numerous studies have revealed that ATII cell senescence and apoptosis are associated with endoplasmic reticulum stress and autophagy, telomere damage, mitochondrial dysfunction, and epigenetic changes, leading to development of pulmonary fibrosis. The activation of LF and deposition of ECM proteins are key steps in the development of IPF. Epigenetic changes and reduced activation of autophagy promote myofibroblast differentiation, ultimately leading to pulmonary fibrosis. Aging AECs promote LF activation by increasing expression of the senescence-associated secretory phenotype (SASP), thereby increasing occurrence and development of pulmonary fibrosis. In short, cellular senescence is an important mechanism of IPF pathogenesis.