Cellular senescence-like features of lung fibroblasts derived from idiopathic pulmonary fibrosis patients.

Hagai Yanai,Albert Shteinberg,Ziv Porat,Vadim E Fraifeld,Rolf Zeische,Arie Budovsky,Alex Braiman

doi:10.18632/aging.100807

Abstract

Idiopathic pulmonary fibrosis (IPF) is an age-related fatal disease with unknown etiology and no effective treatment. In this study, we show that primary cultures of fibroblasts derived from lung biopsies of IPF patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative-stress-induced cytotoxicity or CS; (iii) a CS-like morphology (even at the proliferative phase); and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α-SMA. Our findings suggest that CS could serve as a bridge connecting lung aging and its quite frequent outcome -- pulmonary fibrosis, and be an important player in the disease progression. Consequently, targeting senescent cells offers the potential of being a promising therapeutic approach.

Highlights

It was Élie Metchnikoff who first proposed that “aging is the replacement of noble elements by ignoble ones” [1]
We show that primary cultures of fibroblasts derived from lung biopsies of Idiopathic pulmonary fibrosis (IPF) patients exhibited (i) accelerated replicative cellular senescence (CS); (ii) high resistance to oxidative‐stress‐induced cytotoxicity or CS; (iii) a CS‐like morphology; and (iv) rapid accumulation of senescent cells expressing the myofibroblast marker α‐SMA
The analysis revealed that IPF-derived fibroblasts display a distinct morphology from normal human pulmonary fibroblasts (N-PF) cells (Fig. 2, Table 1): (i) they were larger and had a more irregular shape; (ii) actin density was much lower and there were more cells with a weaker co-localization of actin with the cell membrane; (iii) the vast majority of morphological characteristics of IPF-derived pulmonary fibroblast (IPF-PF) were of markedly higher variability

Summary

Introduction

It was Élie Metchnikoff who first proposed that “aging is the replacement of noble elements by ignoble ones” [1] He suggested that aging results from a progressive replacement of specialized tissues/cells by connective tissue/fibroblasts. One of the most aggressive and enigmatic manifestations of dysbalanced fibroproliferative repair is a disease called Idiopathic Pulmonary Fibrosis (IPF) [3,4,5]. IPF is a progressive lung disease of indefinite etiology in which the pathological hallmark is the heterogeneous alveolar and peribronchial accumulation of scar tissue in the lungs of affected individuals, dominated by an exaggerated non-regenerative repair called “usual interstitial pneumonia” (UIP) [6,7,8]. The only effective treatment currently available for progressive lung fibrosis is lung transplantation [2]

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Conclusion