Fibroblast Senescence in Idiopathic Pulmonary Fibrosis

Abstract

Aging is an inevitable and complex natural phenomenon due to the increase in age. Cellular senescence means a non-proliferative but viable cellular physiological state. It is the basis of aging, and it exists in the body at any time point. Idiopathic pulmonary fibrosis (IPF) is an interstitial fibrous lung disease with unknown etiology, characterized by irreversible destruction of lung structure and function. Aging is one of the most critical risk factors for IPF, and extensive epidemiological data confirms IPF as an aging-related disease. Senescent fibroblasts in IPF show abnormal activation, telomere shortening, metabolic reprogramming, mitochondrial dysfunction, apoptosis resistance, autophagy deficiency, and senescence-associated secretory phenotypes (SASP). These characteristics of senescent fibroblasts establish a close link between cellular senescence and IPF. The treatment of senescence-related molecules and pathways is continually emerging, and using senolytics eliminating senescent fibroblasts is also actively tried as a new therapy for IPF. In this review, we discuss the roles of aging and cellular senescence in IPF. In particular, we summarize the signaling pathways through which senescent fibroblasts influence the occurrence and development of IPF. On this basis, we further talk about the current treatment ideas, hoping this paper can be used as a helpful reference for future researches.

Establishment and Characterization of a Novel Fibroblastic Cell Line (SCI13D) Derived from the Broncho-Alveolar Lavage of a Patient with Fibrotic Hypersensitivity Pneumonitis

“…A consistent number of SCI13D cells show β-galactosidase activity, and mRNA levels of the two cell-cycle inhibitors P16 and P21, typical markers of senescence, were also higher than in the MRC5 cell line used as control. While a close link between senescence and IPF has been previously well established [22,23], robust evidence supporting an association between cellular senescence and progressive fibrosis in fHP is still missing. Interestingly, fibroblasts and epithelial cells within fibroblastic foci observed in lung samples from IPF patients were P16-positive.…”

Application of a High-Content Screening Assay Utilizing Primary Human Lung Fibroblasts to Identify Antifibrotic Drugs for Rapid Repurposing in COVID-19 Patients

“…Nevertheless, it has been reported as attenuating IPF-associated senescent lung fibroblasts and TGFβ-induced peroxide formation via inhibition of NADPH oxidases (NOX). 54 , 55 More specifically, diphenylene-iodonium chloride has been shown to protect from bleomycin-induced lung fibrosis in vivo, quantified in part by reduction of αSMA-expressing myofibroblasts, through inhibition of NOX4. 56 The activity of diphenylene-iodonium chloride includes flavoenzymes in general, 57 as well as a broad-spectrum bacteriocide.…”

From ARDS to pulmonary fibrosis: the next phase of the COVID-19 pandemic?

“…Accelerated aging and cellular senescence have long been implicated in pulmonary fibrosis, and a variety of mechanisms have been associated including both genetic and environmental factors 88 , 89 . In human tissue 88 , 90 , 91 , 92 , animal models 88 , 92 , and in vitro cultures 93 , markers of cellular senescence are increased in pulmonary fibrosis, and this increase is conserved across multiple cell types including epithelial cells and fibroblasts 84 , 95 . Additionally, genetic variants in at least 5 telomere related genes which functionally shorten telomere length have been associated with increased risk of IPF 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 .…”