A Long Discussion of the Role of Senescent Cells in Idiopathic Pulmonary Fibrosis

Senescent cells are constantly created and destroyed throughout life, largely as a result of the replicative senescence that marks the end of life for a somatic cell, the Hayflick limit on cell division. With age, the pace of creation and destruction is disrupted, perhaps largely because the immune system ages to the point at which it falters in all of its tasks, clearance of senescent cells included. Senescent cells accumulate, and while never making up more than a small fraction of all somatic cells in any given tissue, the pro-growth, pro-inflammatory signaling generated by senescent cells is highly disruptive to organ structure and function.

Fibrosis is one of the more noteworthy manifestations of the presence of too many lingering senescent cells. Fibrosis is a malfunction of the normal processes of tissue maintenance, in which excessive collagen is deposited to form scar-like fibrils, disruptive of tissue function. It occurs in the aged kidney, heart, liver, and lungs, and is presently largely irreversible.

A greater degree of fibrosis and consequence loss of function in a given organ passes the threshold to be named as a medical condition, such as the idiopathic pulmonary fibrosis in the lung that is the topic of today's open access paper. It is a long and detailed discussion of what is known of the role of senescent cells in producing lung fibrosis; following a promising clinical trial testing a first generation senolytic therapy in patients with idiopathic pulmonary fibrosis, there is some hope that clearing senescent cells will prove to be a way to reverse fibrosis both in the lung and more generally.

Senescent AECII and the implication for idiopathic pulmonary fibrosis treatment

Idiopathic pulmonary fibrosis (IPF) is an irreversible fibrotic disease in the lungs and is the most common form of idiopathic interstitial pneumonia and idiopathic fibrotic lung disorder. Its biological process is defined as an abnormal repair response to repeated alveolar epithelial cells (AEC) damage and fibroblast-to-myofibroblast differentiation and characterized by the excessive disordered deposition of collagen in the extra- and intra-cellular matrix. Several potential risk factors, such as aging, genetic predisposition, chemical, environmental exposure, and bioenvironmental factor (bacteria and virus), can act on various types of lung cells and enhance the risk of developing IPF.

Of these risk factors, aging is considered an independent risk factor. Even in patients with a genetic predisposition, the onset of IPF seldom occurs before the sixth decade, and the incidence increases exponentially with advancing age. A longitudinal cohort study identifying independent risk factors for the progression of interstitial lung disease has shown that the risk of IPF in people aged 70 or over is 6.9 times that in people aged over 40, confirming that IPF is an age-related disease.

Cell senescence and stem cell exhaustion are the hallmarks of all age-related diseases, as in IPF. Alveolar type II epithelial cells (AECIIs) are the stem cells for the lungs and play a role in maintaining intrapulmonary homeostasis, immunity, and regeneration in the alveoli. Senescent AECIIs secrete high levels of interleukin, interferon, tumor necrosis factor, colony-stimulating factors, growth factors, and chemotactic cytokines, which promote fibroblast-to-myofibroblast differentiation and persistent tissue remodeling.

A recent study has uncovered that pulmonary fibrosis after coronavirus disease 2019 (COVID-19) may be caused by virus-induced AECII senescence. Preventing AECII senescence or targeting senescent cells in patients with COVID-19 can reduce the risk of pulmonary fibrosis. Researchers detected that AECII exhibited high levels of the senescence markers p21 and p16 from patients with IPF. Other numerous studies have shown that AECII senescence promotes the occurrence of IPF. However, pathological mechanisms underlying AECII senescence and specific effects of targeting senescent AECIIs on IPF remain unclear. This review will discuss the mechanism of AECII senescence, which drives the onset and progression of IPF, and highlights the advantages and disadvantages of targeting senescent AECIIs for IPF.