Dataset Information

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival.

ABSTRACT:

Background

Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying circulating prognostic markers. Using a proteomic discovery method followed by ELISA validation in multiple IPF lung compartments and cohorts we explored novel markers of IPF survival.

Methods

In our discovery analysis, agnostic label-free quantitative proteomics differentiated lung tissue protein expression based on survival trajectory (n=10). Following selection of the candidate pathway (neutrophil extracellular trap (NET) formation), we subsequently validated the presence of NETs in the IPF lung microenvironment using fully quantitative assays of known NET remnants in separate IPF cohorts (n=156 and n=52) with bronchoalveolar lavage fluid. We then assessed the correlation of these markers with baseline pulmonary function and survival.

Results

Discovery lung tissue proteomics identified NET formation as significantly associated with poor IPF survival. Using fully quantitative confirmatory tests for reproducibility we confirmed the presence of NET markers in IPF BALF and found significant correlations with worse pulmonary function in both cohorts (p<0.03 and p = 0.04 respectively). In the survival cohort, higher levels of NET markers predicted worse survival after adjusting for gender, age, and baseline physiologic severity (hazard ratio range: 1.79-2.19).

Conclusions

NET markers were associated with disease severity and worse survival in IPF. These findings suggest NET formation contributes to lung injury and decreased survival in IPF and may represent a potential therapeutic target.

SUBMITTER: Matson SM

PROVIDER: S-EPMC10854325 | biostudies-literature | 2024 May

REPOSITORIES: biostudies-literature

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Publications

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival.

Matson Scott M SM Ngo Linh T LT Sugawara Yui Y Fernando Veani V Lugo Claudia C Azeem Imaan I Harrison Alexis A Alsup Alex A Nissen Emily E Koestler Devin D Washburn Michael P MP Rekowski Michaella J MJ Wolters Paul J PJ Lee Joyce S JS Solomon Joshua J JJ Demoruelle M Kristen MK

medRxiv : the preprint server for health sciences 20240502

<h4>Background</h4>Idiopathic pulmonary fibrosis (IPF) leads to progressive loss of lung function and mortality. Understanding mechanisms and markers of lung injury in IPF is paramount to improving outcomes for these patients. Despite the lack of systemic involvement in IPF, many analyses focus on identifying <i>circulating</i> prognostic markers. Using a proteomic discovery method followed by ELISA validation in multiple IPF lung compartments and cohorts we explored novel markers of IPF surviva ...[more]

PMID: 38343853

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Project description:BackgroundNeutrophil extracellular traps (NETs) have been observed in the airway in patients with chronic obstructive pulmonary disease (COPD), but their clinical and pathophysiologic implications have not been defined.ObjectiveWe sought to determine whether NETs are associated with disease severity in patients with COPD and how they are associated with microbiota composition and airway neutrophil function.MethodsNET protein complexes (DNA-elastase and histone-elastase complexes), cell-free DNA, and neutrophil biomarkers were quantified in soluble sputum and serum from patients with COPD during periods of disease stability and during exacerbations and compared with clinical measures of disease severity and the sputum microbiome. Peripheral blood and airway neutrophil function were evaluated by means of flow cytometry ex vivo and experimentally after stimulation of NET formation.ResultsSputum NET complexes were associated with the severity of COPD evaluated by using the composite Global Initiative for Obstructive Lung Disease scale (P < .0001). This relationship was due to modest correlations between NET complexes and FEV1, symptoms evaluated by using the COPD assessment test, and higher levels of NET complexes in patients with frequent exacerbations (P = .002). Microbiota composition was heterogeneous, but there was a correlation between NET complexes and both microbiota diversity (P = .009) and dominance of Haemophilus species operational taxonomic units (P = .01). Ex vivo airway neutrophil phagocytosis of bacteria was reduced in patients with increased sputum NET complexes. Consistent results were observed regardless of the method of quantifying sputum NETs. Failure of phagocytosis could be induced experimentally by incubating healthy control neutrophils with soluble sputum from patients with COPD.ConclusionNET formation is increased in patients with severe COPD and associated with more frequent exacerbations and a loss of microbiota diversity.

Dataset Information

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival.

Background

Methods

Results

Conclusions

Publications

Neutrophil extracellular traps linked to idiopathic pulmonary fibrosis severity and survival.

Similar Datasets

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