Respiratory Symptoms Mediate IL-8-Driven COPD Pathogenesis: A Mechanistic Mediation Analysis in a Community-Based Cross-Sectional Cohort of Chinese Adults

Purpose Chronic obstructive pulmonary disease (COPD) pathogenesis involves interleukin-8 (IL-8)-driven neutrophilic inflammation, but the mediating role of respiratory symptoms in early disease progression remains unquantified. Interleukin-4 (IL-4) has been implicated in counter-regulating inflammatory responses, yet its role in modulating the IL-8-symptom-COPD axis is unclear. Methods In a cross-sectional analysis of 115 participants (34 healthy controls [HC], 55 high-risk individuals [HR], 26 stable COPD [SCOPD]), we measured serum cytokines and hematologic parameters. Analytical approaches included: non-parametric group comparisons (Kruskal-Wallis), Lasso regression for dual-prediction modeling (disease staging and symptom presence), multivariable logistic regression, and bootstrap-mediated mediation analysis (5,000 samples) to explore associations. Results IL-8 levels demonstrated a progressive elevation from healthy controls (HC; median 0.74 pg/mL) to high-risk subjects (HR; 2.20 pg/mL) to stable COPD patients (SCOPD; 5.06 pg/mL; p  < 0.001). Respiratory symptoms mediated 12.23% (95% CI : 1.66% to 27.99%; p  = 0.016) of IL-8's total effect on high-risk status, while IL-8 maintained a significant direct effect (ADE = 54.00; 95% CI : 14.76 to 111.44; p  = 0.002). IL-4 conferred significant protection against symptoms (84% risk reduction; a OR  = 0.16, 95% CI : 0.04 to 0.47; p  = 0.002). The multinomial regression staging model achieved excellent discrimination ( AUCs : HC = 0.946, HR = 0.885, SCOPD = 0.824). Conclusions Respiratory symptoms may actively mediate 12.2% of IL-8's pathogenicity in pre-COPD progression, supporting the concept of an "inflammation-symptom-disease" cascade. Combined IL-8/symptom assessment shows potential to optimize early-risk stratification, while IL-4 emerges as a potential protective therapeutic target.