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

BACKGROUND AND OBJECTIVE: Idiopathic pulmonary fibrosis (IPF) is a chronic progressive interstitial pneumonia of unknown etiology. An increasing number of studies have reported that the incidence of IPF increases with age. Simultaneously, the number of senescent cells increased in IPF. Epithelial cell senescence, an important component of epithelial cell dysfunction, plays a key role in IPF pathogenesis. This article summarizes the molecular mechanisms associated with alveolar epithelial cell senescence and recent advances in the applications of drugs targeting pulmonary epithelial cell senescence to explore novel therapeutic approaches for the treatment of pulmonary fibrosis. METHODS: All literature published in English on PubMed, Web of Science, and Google Scholar were electronically searched online using the following keyword combinations: aging, alveolar epithelial cell, cell senescence, idiopathic pulmonary fibrosis, WNT/β-catenin, phosphatidylinositol-3-kinase/protein kinase B (PI3K/Akt), mammalian target of rapamycin (mTOR), and nuclear factor kappa B (NF-κB). KEY CONTENT AND FINDINGS: We focused on signaling pathways associated with alveolar epithelial cell senescence in IPF, including WNT/β-catenin, PI3K/Akt, NF-κB, and mTOR signaling pathways. Some of these signaling pathways are involved in alveolar epithelial cell senescence by affecting cell cycle arrest and secretion of senescence-associated secretory phenotype-associated markers. We also found that changes in lipid metabolism in alveolar epithelial cells can be induced by mitochondrial dysfunction, both of which contribute to cellular senescence and development of IPF. CONCLUSIONS: 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.