IPF lung fibroblasts have a senescent phenotype

Abstract

The mechanisms of aging that are involved in the development of idiopathic pulmonary fibrosis (IPF) are still unclear. Although it has been hypothesized that the proliferation and activation of human lung fibroblasts (hLFs) are essential in IPF, no studies have assessed how this process works in an aging lung. Our goal was to elucidate if there were age-related changes on primary hLFs isolated from IPF lungs compared with age-matched controls. We investigated several hallmarks of aging in hLFs from IPF patients and age-matched controls. IPF hLFs have increased cellular senescence with higher expression of β-galactosidase, p21, p16, p53, and cytokines related to the senescence-associated secretory phenotype (SASP) as well as decreased proliferation/apoptosis compared with age-matched controls. Additionally, we observed shorter telomeres, mitochondrial dysfunction, and upon transforming growth factor-β stimulation, increased markers of endoplasmic reticulum stress. Our data suggest that IPF hLFs develop senescence resulting in a decreased apoptosis and that the development of SASP may be an important contributor to the fibrotic process observed in IPF. These results might change the existing paradigm, which describes fibroblasts as aberrantly activated cells, to a cell with a senescence phenotype.

Emerging therapies for idiopathic pulmonary fibrosis, a progressive age-related disease

“…Moreover, senescent cells might be harmful and contribute to tissue remodelling, ageing and age-related diseases. In this context, alveolar epithelial and lung fibroblasts with a senescent phenotype are a prominent feature of IPF [111][112][113][114][115] .…”

Oxidative and endoplasmic reticulum stress in respiratory disease

“…Activation of the UPR has been found in both inherited and sporadic IPF and associated with viral infection 13. Additionally, fibroblasts from the lungs of IPF patients show increased ER stress in response to TGFβ 72. IPF‐linked mutations in SFTPC and SFTPA2 cause misfolding of the encoded surfactant proteins and ER stress in type II pneumocytes, providing a direct mechanistic driver for the ER stress in these forms of IPF 13, 73.…”

Sirtuins and Accelerated Aging in Scleroderma

“…Recently, a new paradigm that helps explain the increased prevalence of fibrosis with aging has emerged, suggesting that fibrosis results from the accumulation and decreased turnover of senescent fibroblasts. Fibroblasts from patients with IPF have decreased proliferation and apoptosis than normal fibroblasts, are more resistant to oxidative stress, and exhibit morphological features of cellular senescence [127, 128]. Markers of cellular senescence such as β-galactosidase, p16, and p21 are increased in fibroblasts from patients with IPF and in murine lung fibrosis [128, 129], and the secretome (SASP) of senescent fibroblasts is profibrotic [129].…”

“…Fibroblasts from patients with IPF have decreased proliferation and apoptosis than normal fibroblasts, are more resistant to oxidative stress, and exhibit morphological features of cellular senescence [127, 128]. Markers of cellular senescence such as β-galactosidase, p16, and p21 are increased in fibroblasts from patients with IPF and in murine lung fibrosis [128, 129], and the secretome (SASP) of senescent fibroblasts is profibrotic [129]. Compared to aged matched controls, IPF lung fibroblasts have shorter telomeres, mitochondrial dysfunction, and increased collagen production and endoplasmic reticulum stress in response to TGF-β [128].…”

“…Markers of cellular senescence such as β-galactosidase, p16, and p21 are increased in fibroblasts from patients with IPF and in murine lung fibrosis [128, 129], and the secretome (SASP) of senescent fibroblasts is profibrotic [129]. Compared to aged matched controls, IPF lung fibroblasts have shorter telomeres, mitochondrial dysfunction, and increased collagen production and endoplasmic reticulum stress in response to TGF-β [128]. New therapeutic strategies for fibrosis such as senolytics targeting senescent fibroblasts are emerging and have shown to improve lung function and exercise capacity in bleomycin-mouse models [129].…”