Persistent Airway Uric Acid is Associated with Epithelial Stress Signaling and Macrophage Inflammatory Activation in COPD.

BACKGROUND: Uric acid has been widely studied as a systemic biomarker in pulmonary diseases; however, serum levels are strongly influenced by medication and systemic metabolic status. Whether airway-localized uric acid contributes to epithelial dysfunction in chronic obstructive pulmonary disease (COPD) remains unclear. This study investigated the relationship between persistent mucosal uric acid and epithelial stress signaling, barrier-associated alterations, and macrophage inflammatory activation during acute exacerbations of COPD. METHODS: Paired serum and induced sputum samples were collected from 192 patients with acute exacerbation of COPD (AECOPD) and 194 patients with community-acquired pneumonia (CAP) at baseline and 14 days after therapy. Uric acid concentrations were measured longitudinally. BEAS-2B airway epithelial cells were exposed to uric acid concentrations (200 μg/mL), a concentration corresponding to levels observed in AECOPD sputum. RNA sequencing was performed using three biological replicates per group, followed by Ingenuity Pathway Analysis. Key translational regulators and epithelial barrier-associated proteins were validated by qPCR and Western blotting. Epithelial-macrophage interaction was evaluated using a Transwell co-culture system with cytokine quantification by ELISA. RESULTS: Sputum uric acid was significantly higher in AECOPD (median 120.6 μmol/L) compared with CAP controls and remained elevated after therapy, despite normalization of serum uric acid. In BEAS-2B cells, uric acid exposure induced inflammatory cytokine expression without detectable cytotoxicity. Canonical NF-κB and inflammasome activation were not observed. Transcriptomic analysis identified 2,092 differentially expressed genes and revealed suppression of EIF2 signaling and GCN2-mediated amino acid sensing, indicating activation of epithelial stress responses. Uric acid exposure was associated with altered eIF2α signaling and reduced expression of the tight-junction protein ZO-1, indicating impaired epithelial barrier integrity. In the Transwell co-culture system, macrophages exposed to uric acid-stimulated epithelial signaling showed increased secretion of pro-inflammatory cytokines. CONCLUSION: Persistent airway uric acid may act as a compartment-specific metabolic stressor in COPD, altering epithelial translational stress signaling and barrier-associated ZO-1 expression while promoting macrophage inflammatory activation.