A system biology study of BALF from patients affected by idiopathic pulmonary fibrosis (IPF) and healthy controls

Landi, Claudia; Bargagli, Elena; Carleo, Alfonso; Bianchi, Laura; Gagliardi, Assunta; Prasse, Antje; Perari, M. G.; Refini, Rosa Metella; Bini, Luca; Rottoli, Paola

doi:10.1002/prca.201400001

Cited by 60 publications

(67 citation statements)

References 54 publications

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“…Studies of the IPF proteome to date have focused on bronchoalveolar lavage fluid (BALF) and lung tissue analysis21222324. Novel targets have been reported including CCL2421, and putative molecular pathways have been identified including the unfolded protein response through proteomic studies22.…”

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confidence: 99%

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

O’Dwyer

Norman

Xia

et al. 2017

Sci Rep

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Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal interstitial pneumonia. The disease pathophysiology is poorly understood and the etiology remains unclear. Recent advances have generated new therapies and improved knowledge of the natural history of IPF. These gains have been brokered by advances in technology and improved insight into the role of various genes in mediating disease, but gene expression and protein levels do not always correlate. Thus, in this paper we apply a novel large scale high throughput aptamer approach to identify more than 1100 proteins in the peripheral blood of well-characterized IPF patients and normal volunteers. We use systems biology approaches to identify a unique IPF proteome signature and give insight into biological processes driving IPF. We found IPF plasma to be altered and enriched for proteins involved in defense response, wound healing and protein phosphorylation when compared to normal human plasma. Analysis also revealed a minimal protein signature that differentiated IPF patients from normal controls, which may allow for accurate diagnosis of IPF based on easily-accessible peripheral blood. This report introduces large scale unbiased protein discovery analysis to IPF and describes distinct biological processes that further inform disease biology.

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confidence: 99%

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

O’Dwyer

Norman

Xia

et al. 2017

Sci Rep

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“…Levels of lactic acid, a metabolite generated in response to hypoxia, are high in IPF lung tissue supporting the concept of a hypoxic microenvironment 6 and HIF-1a and 2a have been shown, ex vivo, to be expressed in lung biopsies from patients with IPF, in some but not all reports 7,8 . Additional genomic studies in IPF patients show up-regulation of hypoxia-related gene signatures, including TGF-β 9 , the key fibrotic cytokine in PF, and of the HIF-1α pathways 8,10 .…”

Section: Introductionmentioning

confidence: 99%

Identification of a novel HIF-1α-α_Mβ₂ Integrin-NETosis axis in fibrotic interstitial lung disease

Khawaja

Chong

Sahota

et al. 2020

Preprint

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Neutrophilic inflammation correlates with mortality in fibrotic interstitial lung disease (ILD) however, the underlying mechanisms remain unclear. We aimed to determine whether aberrant neutrophil activation is a feature of ILD and the relative role of hypoxia. We used lung biopsies and bronchoalveolar lavage (BAL) from ILD patients to investigate the extent of hypoxia and neutrophil activation in lungs of patients with ILD. We complemented these findings with ex vivo functional studies of neutrophils from healthy volunteers to determine the effects of hypoxia. We demonstrate for the first time HIF-1α staining in neutrophils and endothelial cells in ILD lung biopsies. Hypoxia enhanced both spontaneous and phorbol 12myristate 13-acetate (PMA)-induced neutrophil extracellular trap (NET) release (NETosis), neutrophil adhesion, and trans-endothelial migration. Hypoxia also increased neutrophil expression of the α M and α X integrin subunits. Interestingly, NETosis was induced by α M β 2 integrin activation and prevented by cation chelation. Finally, NETs were demonstrated in the BAL from ILD patients, and quantification showed significantly increased cell-free DNA content and MPO-citrullinated histone H3 complexes in ILD patients compared to non-ILD controls. Our work indicates that HIF-1α upregulation may augment neutrophil recruitment and activation within the lung interstitium through activation of β 2 integrins. Our results identify a novel HIF-1α-Integrin-NETosis axis for future exploration in therapeutic approaches to fibrotic ILD.

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“…With the advent of ‘–omics’ research, there is growing data showing differences in proteins, RNA, lipids and metabolites between healthy and IPF subjects . These differences have been documented in lung tissue, bronchoalveolar lavage (BALF) and the circulation . Identifying molecules that characterize IPF would be helpful in the diagnosis, prognostication and determination of pathogenic pathways in this condition.…”

Section: Introductionmentioning

confidence: 99%

Analysis by proteomics reveals unique circulatory proteins in idiopathic pulmonary fibrosis

et al. 2019

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Background and objective: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic disease that has a poor 3-year median survival rate with unclear pathophysiology. Radiological features include bibasal, subpleural fibrosis and honeycombing while its pathology is characterized by fibroblastic foci and honeycombing. Proteomic analysis of circulating molecules in plasma may identify factors that characterize IPF and may assist in the diagnosis, prognostication and determination of pathogenic pathways in this condition. Methods: Two independent quantitative proteomic techniques were used, isobaric tags for relative and absolute quantitation (iTRAQ) and multiple reaction monitoring (MRM), to identify differentially expressed plasma proteins in a group of IPF patients in comparison to healthy controls with normal lung function matched for age and gender. Results: Five proteins were identified to be differentially expressed in IPF compared to healthy controls (upregulation of platelet basic protein and downregulation of actin, cytoplasmic 2, antithrombin-III, extracellular matrix protein-1 and fibronectin). Conclusion: This study further validates the combinational use of non-targeted discovery proteomics (iTRAQ) with targeted quantitation by mass spectrometry (MRM) of soluble biomarkers to identify potentially important molecules and pathways for pulmonary diseases such as IPF.

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A system biology study of BALF from patients affected by idiopathic pulmonary fibrosis (IPF) and healthy controls

Cited by 60 publications

References 54 publications

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

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

Identification of a novel HIF-1α-α_Mβ₂ Integrin-NETosis axis in fibrotic interstitial lung disease

Analysis by proteomics reveals unique circulatory proteins in idiopathic pulmonary fibrosis

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A system biology study of BALF from patients affected by idiopathic pulmonary fibrosis (IPF) and healthy controls

Cited by 60 publications

References 54 publications

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

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

Identification of a novel HIF-1α-αMβ2 Integrin-NETosis axis in fibrotic interstitial lung disease

Analysis by proteomics reveals unique circulatory proteins in idiopathic pulmonary fibrosis

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Identification of a novel HIF-1α-α_Mβ₂ Integrin-NETosis axis in fibrotic interstitial lung disease