Circulatory heavy metals (cadmium, lead, mercury, and chromium) inversely correlate with plasma GST activity and GSH level in COPD patients and impair NOX4/Nrf2/GCLC/GST signaling pathway in cultured monocytes

Abstract

This study aims to examine the hypothesis that circulatory heavy metals may be associated with lung function decline and lower plasma GST activity and GSH level in COPD patients via activating monocytes mediated by impairing the NOX4/Nrf2/GCLC/GST signaling pathway. Results showed that the blood levels of heavy metals (cadmium, lead, mercury, and chromium) were significantly higher in COPD patients of coal mine site compared to the healthy controls. The levels of heavy metals in COPD patients were significantly and negatively correlated with lung function, GST activity, and GSH level. Using flowcytometry, fluorescence spectroscopy, and immunoblotting studies we have further demonstrated that treatment with individual heavy metals dose-dependently increased the NOX4 protein expression, intracellular ROS production, and decreased the Nrf2, GCLC, and GST protein expression, GST activity, and GSH level in THP-1 monocytes. None of the treatment caused any change in cell viability compared to control. In conclusion, this study suggests that circulatory heavy metals in COPD patients of coal mine site weakened the lung function, decreased the plasma GST activity and GSH level via impairing the NOX4/Nrf2/GCLC/GST signaling pathway in monocytes, which may cause monocyte activation and initiate the COPD pathophysiology.