Proteomic profiling reveals immunologic mediators of endotoxin-related lung function decline: a longitudinal prospective study in textile workers

Endotoxin is a major pathogenic component of cotton dust in the textile industry. While airborne endotoxin is associated with lung function decline, the underlying molecular mechanisms remain unclear. Proteomic profiling could provide important insights into the pathways that drive the harmful respiratory effects of endotoxin. We conducted serum proteomic profiling of 221 endotoxin-exposed cotton workers and 192 endotoxin-free silk workers from the longitudinal cohort of the Shanghai Textile Worker Study. Using blood samples collected in 2016, proteins were quantified by data-independent acquisition mass spectrometry and genotyping was assessed using low-pass whole genome sequencing. Forced expiratory volume in 1 s (FEV-1) was measured in 2011 and 2016. We used adjusted regression to identify differentially expressed proteins (DEPs) between the exposed and control groups. Causal mediation analyses were performed to identify protein mediators. Mendelian Randomization (MR) analyses provided causal estimates of protein effects on lung function change. Among 2,962 quantified proteins, we identified 224 proteins that were differentially expressed between cotton and silk workers (Bonferroni p < 0.05). Top enriched pathways associated with DEPs were the complement and coagulation cascades (KEGG: hsa04610) and the chemokine signaling pathway (KEGG: hsa04062). Adaptive immune proteins collectively mediated endotoxin-related lung function decline (binomial p = 9.63 × 10⁻⁹⁷). Two immunoglobulin domain proteins significantly (Bonferroni p < 0.05) mediated endotoxin effects on lung function change: Epididymis luminal protein 180 (HEL180) and IGL c3728_light_IGKV4-1_IGKJ1 (IGL c3728), with 46.4% (p = 0.04) and 46.9% (p = 0.05) proportion of the total effect that was mediated. MR estimates demonstrated that every 2-fold decrease in HEL180 and IGL c3728 expression was associated with an FEV-1 decline of 1.90 ml/year (95% CI: [0.79, 3.02]) and 2.36 ml/year (95% CI: [1.68, 3.02]), respectively. Using a trans-omic approach, our findings suggest that chronic endotoxin exposure suppresses immunoglobulin domain proteins, weakens adaptive immunity, and accelerates lung function decline. These findings provide greater precision in understanding biological mechanisms underlying endotoxin-related respiratory dysfunction.