Anthrahydroquinone-2,6-Disulfonate Restores Lung Function in COPD Through Keap1/Nrf2 Pathway Activation.

OBJECTIVE

Chronic obstructive pulmonary disease (COPD), the third leading cause of death globally, is strongly driven by oxidative damage, contributing to lung function decline and high mortality. Despite advances in understanding oxidative stress in COPD pathogenesis, effective strategies to mitigate oxidative damage and normalize lung function remain a challenge. Anthrahydroquinone-2,6-disulfonate (AHQDS) has potent antioxidant properties, but its ability to alleviate persistent airway oxidative damage and normalize lung function in COPD patients is not fully elucidated. This study aimed to investigate the therapeutic effects of AHQDS on COPD by exploring its mechanisms involving the Keap1-Nrf2 pathway via in vivo and in vitro models.

METHODS

This study induced COPD-like pathology by using LPS in combination with CS / CSE, establishing both in vivo and in vitro models to evaluate the effects of AHQDS on lung function, histopathology, oxidative stress markers, levels of inflammatory cytokines, and apoptosis. Molecular docking predicted the interaction between AHQDS and Keap1-Nrf2 proteins, which was confirmed by immunoblotting.

RESULTS

AHQDS treatment significantly mitigated lung tissue injury and restored lung function parameters (MMEF, PEF) in COPD model rats. This treatment upregulated the expression of antioxidant enzymes (SOD, CAT, and GSH-PX) and reduced the levels of inflammatory cytokines (TNF-α, IL-6, IL-1β, and IL-33), ROS, and the total number of apoptotic cells (Annexin V+). Following AHQDS treatment, the expression of the Nrf2 protein was increased, and the expression of its downstream antioxidant proteins, HO-1 and NQO1, was also upregulated. Molecular docking analysis revealed a high binding affinity between AHQDS and Keap1-Nrf2 protein (binding energy: -8.0 kcal/mol).

CONCLUSION

AHQDS promotes the body's capacity to counteract oxidative damage and reduces inflammatory cytokine levels by activating the Keap1‒Nrf2 pathway, thereby normalizing lung function in COPD.