# Neutrophil degranulation in the lung microenvironment linked to idiopathic pulmonary fibrosis severity and survival

## TL;DR

Neutrophil degranulation in the lungs is linked to worse outcomes in idiopathic pulmonary fibrosis, suggesting a new target for treatment and risk assessment.

## Contribution

Identifies neutrophil degranulation as a lung-specific mechanism driving IPF severity and survival.

## Key findings

- Neutrophil degranulation is the top pathway associated with poor survival in IPF lung tissue.
- Bronchoalveolar markers like DNA-myeloperoxidase complexes and calprotectin predict worse survival.
- Lung-specific markers correlate with reduced lung function across multiple IPF cohorts.

## Abstract

Idiopathic pulmonary fibrosis (IPF) causes progressive respiratory failure with variable survival trajectories among patients. Neutrophils accumulate in IPF lungs, but their mechanistic contribution to disease progression remains to be determined. We applied label-free quantitative proteomics to IPF lung tissue (n = 10) and bronchoalveolar lavage fluid (BALF) (n = 50) from patients with distinct survival outcomes. Neutrophil degranulation emerged as the pathway most strongly associated with poor survival in lung tissue and second most significant in BALF. We validated these findings using absolute quantification of neutrophil degranulation markers in two independent IPF cohorts (n = 156 and n = 52). Higher BALF levels of extracellular DNA, DNA-myeloperoxidase complexes, calprotectin, and neutrophil elastase predicted worse survival (hazard ratios: 1.79–2.19) and correlated with reduced lung function. These results identify neutrophil degranulation as a compartment-specific mechanism of lung injury in IPF that may guide therapeutic development and risk stratification.

•Proteomics links neutrophil degranulation to worse survival in lung fibrosis•Bronchoalveolar markers predict poor survival independent of clinical scores•Bronchoalveolar markers associate with lower lung function across cohorts•Blood markers were not predictive, highlighting lung-specific activity

Proteomics links neutrophil degranulation to worse survival in lung fibrosis

Bronchoalveolar markers predict poor survival independent of clinical scores

Bronchoalveolar markers associate with lower lung function across cohorts

Blood markers were not predictive, highlighting lung-specific activity

Fibrosis; Body substance sample; Components of the immune system; Proteomics