Erratum: The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

O’Dwyer, David N.; Norman, Katy C.; Meng, Xiangjian; Huang, Yong; Gurczynski, Stephen J.; Ashley, Shanna L.; White, Eric S.; Flaherty, Kevin R.; Martínez, Fernando J.; Murray, Susan; Noth, Imre; Arnold, Kelly B.; Moore, Bethany B.

doi:10.1038/srep46860

Cited by 3 publications

(2 citation statements)

References 1 publication

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“…This analysis shows induction of pro-fibrotic pathways such as embryonic morphogenesis, ECM organization, interleukin signalling and downregulation of pro-epithelial injury signalling pathways such as surfactant metabolism [35][36][37][38] . Interestingly, proteomic analysis of peripheral blood from IPF patients has been shown to have downregulation of cell proliferation 39 pathways, similar to the proteome of TGFß1 treated hPCLS analysed in our study. Furthermore, we curated the significantly regulated proteins on day 13 in TGFß1 treated hPCLS (vs day 13, unstimulated hPCLS) to those of different cell type markers listed in LGEA web portal 22,23 .…”

Section: Induction Of Pro-fibrotic Signalling Upon Tgfß1 Stimulation supporting

confidence: 74%

Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices

Khan¹,

Poeckel²,

Halavatyi

et al. 2019

Preprint

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Fibrosis can affect any organ resulting in the loss of tissue architecture and function with often life-threatening consequences. Pathologically, fibrosis is characterised by expansion of connective tissue due to excessive deposition of extracellular matrix proteins (ECM), including the fibrillar forms of collagen. A significant hurdle for discovering cures for fibrosis is the lack of suitable models and techniques to quantify mature collagen deposition in tissues. Here we have extensively characterized an ex-vivo cultured human lung derived, precision-cut lung slices model (hPCLS) using live fluorescence light microscopy as well as mass spectrometry-based techniques to obtain a proteomic and metabolomic fingerprint. Using an integrated approach of multiple readouts such as quantitative label-free Second Harmonic Generation (SHG) imaging to measure fibrillar collagen in the extracellular matrix and ELISA-based methods to measure soluble ECM biomarkers, we investigated TGFbeta1-mediated pro-fibrotic signalling in hPCLS. We demonstrate that hPCLS are viable and metabolically active with mesenchymal, epithelial, endothelial, and immune cells surviving for at least two weeks in ex vivo culture. Analysis of hPCLS-conditioned supernatants showed strong induction of ECM synthesis proteins P1NP and fibronectin upon TGFb stimulation. Importantly, this effect translated into an increased deposition of fibrillar collagen in ECM of cultured hPCLS as measured by a novel quantitative SHG-based imaging method only following addition of a metalloproteinase inhibitor (GM6001). Together the data show that an integrated approach of measuring soluble pro-fibrotic markers and quantitative SHG-based analysis of fibrillar collagen is a valuable tool for studying pro-fibrotic signalling and testing anti-fibrotic agents.

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Section: Induction Of Pro-fibrotic Signalling Upon Tgfß1 Stimulation supporting

confidence: 74%

Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices

Khan¹,

Poeckel²,

Halavatyi

et al. 2019

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, proteomic analysis of peripheral blood done elsewhere from IPF patients has been shown to have downregulated cell proliferation 45 pathways, similar to the proteome of TGFß1 treated hPCLS analysed in our study. The 109 proteins significantly regulated ( Figure S4A) upon TGFß1 treatment were curated against LGEA database for cell-type specific markers (Table S5).…”

Section: Induction Of Pro-fibrotic Signalling Upon Tgfß1 Stimulation supporting

confidence: 72%

An integrated multiomic and quantitative label-free microscopy-based approach to study pro-fibrotic signalling in ex vivo human precision-cut lung slices

Khan

Poeckel²,

Halavatyi

et al. 2020

Eur Respir J

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Fibrosis can affect any organ resulting in the loss of tissue architecture and function with often life-threatening consequences. Pathologically, fibrosis is characterised by expansion of connective tissue due to excessive deposition of extracellular matrix proteins (ECM), including the fibrillar forms of collagen. A significant limitation for discovering cures for fibrosis is the availability of suitable human models and techniques to quantify mature fibrillar collagen deposition as close as possible to human physiological conditions. Here we have extensively characterised an ex vivo cultured human lung tissue-derived, precision-cut lung slices model (hPCLS) using label-free second harmonic (SHG) light microscopy to quantify fibrillar collagen deposition and mass spectrometry-based techniques to obtain a proteomic and metabolomic fingerprint of hPCLS in ex vivo culture.We demonstrate that hPCLS are viable and metabolically active with mesenchymal, epithelial, endothelial, and immune cell types surviving for at least 2 weeks in ex vivo culture. Analysis of hPCLS-conditioned supernatants showed a strong induction of pulmonary fibrosis-related ECM proteins upon TGFß1 stimulation. This upregulation of ECM proteins was not translated into an increased deposition of fibrillar collagen. In support of this observation, we revealed the presence of a pro-ECM degradation activity in our ex vivo cultures of hPCLS, inhibition of which by metalloproteinase inhibitor resulted in increased collagen deposition in response to TGFß1 stimulation. Together the data show that an integrated approach of measuring soluble pro-fibrotic markers alongside quantitative SHG-based analysis of fibrillar collagen is a valuable tool for studying pro-fibrotic signalling and testing antifibrotic agents.

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Citrullinated and MMP-degraded vimentin is associated with chronic pulmonary diseases and genetic variants in PADI3/PADI4 and CFH in postmenopausal women

Bager,

Blair,

Tang

et al. 2023

Sci Rep

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Citrullinated vimentin has been linked to several chronic and autoimmune diseases, but how citrullinated vimentin is associated with disease prevalence and genetic variants in a clinical setting remains unknown. The aim of this study was to obtain a better understanding of the genetic variants and pathologies associated with citrullinated and MMP-degraded vimentin. Patient Registry data, serum samples and genotypes were collected for a total of 4369 Danish post-menopausal women enrolled in the Prospective Epidemiologic and Risk Factor study (PERF). Circulating citrullinated and MMP-degraded vimentin (VICM) was measured. Genome-wide association studies (GWAS) and phenome wide association studies (PheWAS) with levels of VICM were performed. High levels of VICM were significantly associated with the prevalence of chronic pulmonary diseases and death from respiratory and cardiovascular diseases (CVD). GWAS identified 33 single nucleotide polymorphisms (SNPs) with a significant association with VICM. These variants were in the peptidylarginine deiminase 3/4 (PADI3/PADI4) and Complement Factor H (CFH)/KCNT2 gene loci on chromosome 1. Serum levels of VICM, a marker of citrullinated and MMP-degraded vimentin, were associated with chronic pulmonary diseases and genetic variance in PADI3/PADI4 and CFH/ KCNT2. This points to the potential for VICM to be used as an activity marker of both citrullination and inflammation, identifying responders to targeted treatment and patients likely to experience disease progression.

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Erratum: The peripheral blood proteome signature of idiopathic pulmonary fibrosis is distinct from normal and is associated with novel immunological processes

Cited by 3 publications

References 1 publication

Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices

Multiomic and quantitative label-free microscopy-based analysis ofex vivoculture and TGFbeta1 stimulation of human precision-cut lung slices

An integrated multiomic and quantitative label-free microscopy-based approach to study pro-fibrotic signalling in ex vivo human precision-cut lung slices

Citrullinated and MMP-degraded vimentin is associated with chronic pulmonary diseases and genetic variants in PADI3/PADI4 and CFH in postmenopausal women

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