Reviewing Cellular Senescence in Idiopathic Pulmonary Fibrosis

Fibrosis is the excessive deposition of extracellular matrix, forming scar-like structures that are disruptive to tissue function. It is a feature of aging in many organs, such as heart, liver, kidney, and lungs, and when particularly pronounced it is declared to be fibrotic disease. So far medical science has struggled to make much headway in the reversal of fibrosis once it is established, which makes these conditions particularly threatening.

Fibrosis is connected to the chronic inflammation characteristic of old age, and in recent years evidence has amassed for senescent cells to drive fibrosis. Senescent cells increase in number with age in tissues throughout the body, and produce pro-growth, pro-inflammatory signaling. When tissue is injured, senescent cells emerge for a short time to help coordinate regeneration. In later life, this constant signaling alters cell behavior for the worse, disrupting normal tissue maintenance to encourage pathologies like fibrosis to develop.

Selectively clearing senescent cells via the use of senolytic drugs has been shown in animal studies to reverse fibrosis in a number of different organs. One of the first small human clinical trials of senolytic drugs targeted patients with idiopathic pulmonary fibrosis. It is this condition, and the senescent cells that may drive its onset and development, that are the subject of today's open access review paper.

Molecular mechanisms of alveolar epithelial cell senescence and idiopathic pulmonary fibrosis: a narrative review

Idiopathic pulmonary fibrosis (IPF) is a commonly diagnosed chronic, progressive, and fibrotic interstitial pneumonia that accounts for 20-30% of interstitial lung diseases. It usually occurs in middle-aged and elderly individuals. It is now generally accepted that persistent alveolar epithelial damage and repair dysregulation are the principal mechanisms leading to progressive pulmonary fibrosis.

Repetitive epithelial cell injury and deficiencies in regeneration result in the release of mediators, including cytokines, chemokines, fibrogenic factors, coagulant proteins, oxidants, and regulators of apoptosis. This leads to the recruitment, proliferation, and activation of interstitial fibroblasts to form fibrotic foci. Additionally, excessive deposition of the extracellular matrix leads to destruction of lung parenchymal structures. Interestingly, a variety of cells, including alveolar epithelial type II cells (ATII) and fibroblasts, can drive IPF. Regardless of the driver cell types, senescence leads to a decrease in the repair capacity of damaged alveolar epithelium. As a result, fibrous tissue replaces the damaged alveolar epithelium.

From a histopathological point of view, IPF formation is a dynamic process involving complex interactions among epithelial cells, fibroblasts, immune cells (such as macrophages and T lymphocytes), and endothelial cells. Alveolar epithelial cells undergo cytoskeletal remodeling and acquire a mesenchymal phenotype through epithelial-mesenchymal transition (EMT), in which epithelial cells lose intercellular attachment, polarity, and epithelial-specific markers, leading to fibrosis.

Some investigators have identified ATII as a major player in the synthesis of transforming growth factor-beta (TGF-β) and tumor necrosis factor-alpha (TNF-α) in lung biopsies from patients with IPF. In the process of organ fibrosis formation, including pulmonary fibrosis, TGF-β acts as the master switch for the induction of the EMT process. In particular, TGF-β mediates fibrous proliferative effects by inducing apoptosis in alveolar epithelial type I (ATI) cells. However, there is no direct evidence that TGF-β promotes IPF by inducing senescence in the alveolar epithelial cells.

In the lungs of patients with IPF, the ability of ATII cells to transdifferentiate into ATI cells is diminished. Emerging evidence also suggests that triggering ATII senescence can promote IPF. Therefore, studying the mechanisms of cellular senescence in the lung microenvironment is crucial to understand IPF pathogenesis and progression. Decreasing senescent alveolar epithelial cells may be a promising strategy for the treatment of IPF. Therefore, further investigations into new treatments of IPF by applying inhibitors of relevant signaling pathways, as well as senolytic drugs, are warranted.

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