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

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 (<i>n</i> = 10) and bronchoalveolar lavage fluid (BALF) (<i>n</i> = 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 (<i>n</i> = 156 and <i>n</i> = 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.