Transcriptional regulatory model of fibrosis progression in the human lung

McDonough, John E.; Ahangari, Farida; Li, Qin; Jain, Siddhartha; Verleden, Stijn E.; Herazo-Maya, José D.; Vukmirovic, Milica; DeIuliis, Giuseppe; Tzouvelekis, Argyrios; Tanabe, Naoya; Chu, Fanny; Yan, Xiting; Verschakelen, Johny; Homer, Robert J.; Manatakis, Dimitris V.; Zhang, Junke; Ding, Jun; Maes, Karen; Sadeleer, Laurens J. De; Vos, Robin; Neyrinck, Arne; Benos, Panayiotis V.; Bar‐Joseph, Ziv; Tantin, Dean; Hogg, James C.; Vanaudenaerde, Bart M.; Wuyts, Wim; Kaminski, Naftali

doi:10.1172/jci.insight.131597

Cited by 130 publications

(138 citation statements)

References 61 publications

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“…Consistent with previous reports in IPF epithelial cells, our findings identified the activation of transcriptional pathways associated with cell injury and repair in chronically injured AE2 cells. (27,56). There are similar findings in the transcriptome analysis between our data and one of IPF epithelial cells (32,56).…”

Section: Discussionsupporting

confidence: 89%

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: 89%

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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“…It was also significantly overexpressed at the baseline level in IPF-HLFs in comparison to the N-HLFs. Interestingly, in a large recent study by McDonough et al that characterized the transcriptional regulatory model of fibrosis in the human lung, the GREM1 was found to be one of the four upregulated genes in IPF that also correlated with disease severity [45].…”

Section: Discussionmentioning

confidence: 99%

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

et al. 2020

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Background: Idiopathic pulmonary fibrosis (IPF) is a chronic and ultimately fatal disease characterized by a progressive decline in lung function. Fibrotic diseases, such as IPF, are characterized by uncontrolled activation of fibroblasts. Since the microenvironment is known to affect cell behavior, activated fibroblasts can in turn activate healthy neighboring cells. Thus, we investigated IPF paracrine signaling in human lung fibroblasts (HLFs) derived from patients with IPF. Methods: Primary human fibroblast cultures from IPF (IPF-HLF) and control donor (N-HLF) lung tissues were established and their supernatants were collected. These supernatants were then added to N-HLFs for further culture. Protein and RNA were extracted from IPF/ N-HLFs at baseline. Interleukin-6 (IL-6) and TGF-β-related signaling factors (e.g. STAT3, Smad3) were evaluated by western blot and qPCR. IL-6 levels were measured by ELISA. IL-6 signaling was blocked by Tocilizumab (TCZ) (10 ng/ml).Results: IPF-HLFs were found to significantly overexpress IL-6 receptor (IL-6R), suppressor of cytokine signaling 3 (SOCS3), phospho-STAT3-Y705 and phospho-Smad3 in comparison to N-HLFs (p < 0.05). In addition, they were found to proliferate faster, secrete more IL-6 and express higher levels of the soluble IL-6R. IPF-HLF increased proliferation was inhibited by TCZ. Moreover, IPF-HLF derived supernatants induced both direct and indirect STAT3 activation that resulted in Smad3 phosphorylation and elevated Gremlin levels in N-HLFs. These effects were also successfully blocked by TCZ.Conclusions: IPF-HLF paracrine signaling leads to IL-6R overexpression, which in turn, affects N-HLF survival. The IL-6/STAT3/ Smad3 axis facilitates cellular responses that could potentially promote fibrotic disease. This interplay was successfully blocked by TCZ.

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“…To follow up on these observations, we considered the possibility that ACE2 expression was commonly upregulated by lung diseases and/or carcinogen exposure. Indeed, we observed increased ACE2 expression in two cohorts of patients with idiopathic pulmonary fibrosis (IPF) 31,32 , a lung disease strongly associated with prior cigarette exposure (Figure S2A-B) 33 . However, ACE2 was not up-regulated in lung cells from a large cohort of patients with asthma or from patients with the lung disease sarcoidosis (Figure S2C-D) 34,35 .…”

Section: Introductionmentioning

confidence: 94%

Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

Smith

Sausville

Girish

et al. 2020

Preprint

100

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The coronavirus SARS-CoV-2 has infected more than 600,000 people and has overwhelmed hospital systems around the world. However, the factors mediating fatal SARS-CoV-2 infections are poorly understood. Here, we show that cigarette smoke causes a dose-dependent upregulation of Angiotensin Converting Enzyme 2 (ACE2), the SARS-CoV-2 receptor, in rodent and human lungs. Using single-cell sequencing data, we demonstrate that ACE2 is expressed in a subset of epithelial cells that line the respiratory tract, including goblet cells, club cells, and alveolar type 2 cells. Chronic smoke exposure triggers a protective expansion of mucus-secreting goblet cells and a concomitant increase in ACE2 expression. In contrast, quitting smoking causes a decrease in lung ACE2 levels. Taken together, these results may partially explain why smokers are particularly likely to develop severe SARS-CoV-2 infections, and they suggest that quitting smoking could lessen coronavirus susceptibility.

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Transcriptional regulatory model of fibrosis progression in the human lung

Cited by 130 publications

References 61 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

TGF-β pathway activation by idiopathic pulmonary fibrosis (IPF) fibroblast derived soluble factors is mediated by IL-6 trans-signaling

Cigarette smoke exposure and inflammatory signaling increase the expression of the SARS-CoV-2 receptor ACE2 in the respiratory tract

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