Background: The pathogenetic role of air pollution in COPD is poorly understood. Our previous proteomic study identified inter-alpha-trypsin inhibitor heavy chain 4 (ITIH4) as a PM-associated serum protein. Objective: To study the clinical and pathogenetic role of ITIH4 in COPD.Methods: 221 participants were enrolled (COPD, n = 178; Healthy, n = 41). Protein expression by ELISA and IHC were correlated with clinical factors. Primary human small airway epithelial cells (HSAEpC) and BEAS2B cells were used to investigate the mechanism. Results: Mean daily exposure of PM₁₀ (Spearman?s correlation coefficient rs = 0.25, p < 0.001) and PM_2.5 (rs = 0.28, p < 0.001) were positively correlated with severity of emphysema, determined by quantitative HRCT (LAA%). Serum levels of ITIH4 was reduced in patients with COPD and were positively correlated with FEV1% (rs = 0.364, p < 0.001), and negatively correlated with LAA% (rs = ?0.487, p < 0.001), PM_2.5 (rs = ?0.412, p < 0.001), and PM₁₀ (rs = ?0.373, p < 0.001). Reduced ITIH4 (0.23-fold) in the lung tissue of COPD (n= 78) was negatively correlated with apoptosis (active caspase-3, rs=-0.563, p<0.001). COPD HSAEpC had enhanced PM_2.5- and H₂O₂-induced JNK activation and apoptosis, being robustly inhibited by over-expression of ITIH4 or the JNK inhibitor SP600125 (10?M). ITIH4 overexpression also protected ?-catenin from downregulation that was not affected by SP600125. Conclusion: ITIH4 reduction is correlated with long-term PM exposure and emphysema in patients with COPD, and might be critically implicated in the pathogenesis of emphysema through impairment in protection from JNK-mediated epithelial apoptosis and prevention from ?-catenin downregulation.