Background: Chronic Obstructive Pulmonary Disease (COPD) is a major cause of morbidity and mortality worldwide. Pulmonary microvascular endothelial glycocalyx (PMEG) has been found to be significantly reduced in COPD, but the mechanism, cause, and effect of the reduction on COPD progression are inconclusive. Objective: This study aims to explore the mechanisms and consequences underlying PMEG degradation in COPD. Additionally, we strive to ascertain whether Tongxinluo (TXL)'s protective role in COPD is mediated through the preservation of PMEG integrity. Methods: A staged cigarette smoke (CS) exposure model was employed to investigate the timeline, trajectory, mechanisms, and causes of glycocalyx degradation, with in vitro validation. The in vivo glycocalyx degradation model was induced by intravenous injection of glycocalyx hydrolase along with CS exposure. The protective effect of TXL on glycocalyx integrity was examined in CS-exposed mice treated with TXL. Results: PMEG degradation occurs as early as 2 weeks after CS exposure and worsens as the disease advances. Multiple glycocalyx degrading enzyme upregulation at different time points collectively results in consistent glycocalyx component degradation. Mechanistically, CS or reactive oxygen species (ROS) exposure elevates proinflammatory cytokine secretion, leading to an increase in glycocalyx hydrolysis expression and subsequent PMEG degradation on the endothelial cell (EC) surface. PMEG degradation further promotes inflammatory cell infiltration and accelerates endothelial apoptosis, ultimately driving disease progression in COPD. TXL alleviates oxidative stress, reverses the upregulation of PMEG degrading enzyme, preserves PMEG integrity, reduces endothelial cell apoptosis, and mitigates COPD pathology. Conclusion: In summary, this study provides groundbreaking insights into the role of PMEG degradation in COPD pathogenesis and introduces TXL as a novel therapeutic agent with the potential to preserve PMEG integrity and mitigate COPD progression. These findings significantly advance our understanding of COPD and offer inno-vative directions for future research and therapeutic development.