Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cuevas-Mora, Karina; Roque, Willy; Sales, Dominic; Jd, Ritzenthaler; Torres-Gonzales, E; Aj, Halayko; Rosas, IO; Roman, Jesse; Romero, Freddy

doi:10.1101/2020.04.10.036327

Cited by 3 publications

(2 citation statements)

References 58 publications

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“…Previous studies have reported reduced Hsp70 levels in lung fibroblasts of IPF patients (43). Consistent with this, we recently demonstrated that the decline of HSF1 activation plays a central role in reducing this chaperone levels in these cells (10). Additionally, Hsp70-knockout mice demonstrated accelerated pulmonary fibrosis after bleomycin administration (43).…”

Section: Discussionsupporting

confidence: 81%

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Roque

Cuevas-Mora²,

Sales³

et al. 2020

Preprint

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The current hypothesis suggests that Idiopathic pulmonary fibrosis (IPF) arises as a result of chronic injury to alveolar epithelial cells and aberrant activation of multiple signaling pathways. Dysfunctional IPF lung epithelium manifests many hallmarks of aging tissues, including cellular senescence, mitochondrial dysfunction, metabolic dysregulation, and loss of proteostasis. Unfortunately, this disease is often fatal within 3-5 years from diagnosis, and there is no effective treatment. One of the major limitations to the development of novel treatments in IPF is that current models of the disease fail to resemble several features seen in elderly IPF patients. In this study, we sought to develop an in vitro epithelial injury model using repeated low levels of bleomycin to mimic the phenotypic and functional characteristics of the IPF lung epithelium. Consistent with the hallmarks of the aging lung epithelium, we found that chronic-injured epithelial cells exhibited features of senescence cells, including an increase in β-galactosidase staining, induction of p53 and p21, mitochondrial dysfunction, excessive ROS production, and proteostasis alteration. Next, combined RNA sequencing, untargeted metabolomics, and lipidomics were performed to investigate the dynamic transcriptional, metabolic, and lipidomic profiling of our in vitro model. We identified that a total of 8,484 genes with different expression variations between the exposed group and the control group. According to our GO enrichment analysis, the down-regulated genes are involved in multiple biosynthetic and metabolic processes. In contrast, the up-regulated genes in our treated cells are responsible for epithelial cell migration and regulation of epithelial proliferation. Furthermore, metabolomics and lipidomics data revealed that overrepresented pathways were amino acid, fatty acid, and glycosphingolipid metabolism. This result suggests that by using our in vitro model, we were able to mimic the transcriptomic and metabolic alterations of those seen in the lung epithelium of IPF patients. We believe this model will be ideally suited for use in uncovering novel insights into the gene expression and molecular pathways of the IPF lung epithelium and performing screening of pharmaceutical compounds.

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Section: Discussionsupporting

confidence: 81%

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Roque

Cuevas-Mora²,

Sales³

et al. 2020

Preprint

Self Cite

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“…In contrast, HSP90 is overexpressed in IPF lung fibroblasts and inhibition of this chaperone attenuated the progression of pulmonary fibrosis. We recently demonstrated that reduction in HSF1 activation plays a central role in reducing chaperone levels in lung fibroblasts [ 49 ]. In this study, we show that HSF1 activation, was significantly reduced in injured cells.…”

Section: Discussionmentioning

confidence: 99%

A model of the aged lung epithelium in idiopathic pulmonary fibrosis

Shaghaghi¹,

Cuevas-Mora²,

Para³

et al. 2021

Aging

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Idiopathic pulmonary fibrosis (IPF) is an age-related disorder that carries a universally poor prognosis and is thought to arise from repetitive micro injuries to the alveolar epithelium. To date, a major factor limiting our understanding of IPF is a deficiency of disease models, particularly in vitro models that can recapitulate the full complement of molecular attributes in the human condition. In this study, we aimed to develop a model that more closely resembles the aberrant IPF lung epithelium. By exposing mouse alveolar epithelial cells to repeated, low doses of bleomycin, instead of usual one-time exposures, we uncovered changes strikingly similar to those in the IPF lung epithelium. This included the acquisition of multiple phenotypic and functional characteristics of senescent cells and the adoption of previously described changes in mitochondrial homeostasis, including alterations in redox balance, energy production and activity of the mitochondrial unfolded protein response. We also uncovered dramatic changes in cellular metabolism and detected a profound loss of proteostasis, as characterized by the accumulation of cytoplasmic protein aggregates, dysregulated expression of chaperone proteins and decreased activity of the ubiquitin proteasome system. In summary, we describe an in vitro model that closely resembles the aberrant lung epithelium in IPF. We propose that this simple yet powerful tool could help uncover new biological mechanisms and assist in developing new pharmacological tools to treat the disease.

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Heat shock proteins in pulmonary fibrosis: pawns of cell homeostasis

Barboza

2022

American Journal of Physiology-Cell Physiology

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Idiopathic lung fibrosis (IPF) is a fatal disease that primarily affects the elderly. Up to date, the specific pathophysiology of IPF remains unknown. However, it is theorized to be caused by chronic repetitive injuries to the alveolar epithelium, eventually exhausting the stem cell capacity and activating pathological pathways. Heat shock proteins (HSPs), a category of stress response proteins, are also suggested to contribute to IPF pathophysiology. Furthermore, HSPs are key components in the regulation of cell homeostasis and act as chaperones for a multitude of new proteins. This review thoroughly evaluates the roles that specific HSPs, HSP90, HSP70, and HSP47, have in the fibrotic process. A close look into the roles of these HSPs in IPF pathophysiology will give valuable insight into the future of IPF treatment and prevention.

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Impaired HSF1 transactivation drives proteostasis collapse and senescent phenotype of IPF lung fibroblast

Cited by 3 publications

References 58 publications

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

Transcriptomics, metabolomics and lipidomics of chronically injured alveolar epithelial cells reveals similar features of IPF lung epithelium

A model of the aged lung epithelium in idiopathic pulmonary fibrosis

Heat shock proteins in pulmonary fibrosis: pawns of cell homeostasis

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