COPD and the effect of low-dose cadmium, a highly toxic metal, on airway epithelial cells

Exposure to cigarette smoke is associated with the development and severity of chronic obstructive pulmonary disease, or COPD, which is the third leading cause of death worldwide.

Cigarette smoke contains 2 to 3 micrograms of cadmium, a highly toxic metal and environmental pollutant, per cigarette. Burning tobacco releases cadmium oxide which can be adsorbed onto smoke microparticles that penetrate deep into the lungs. Additionally, the body is unable to eliminate cadmium, which accumulates in long-term smokers.

In a Scientific reports study, researchers from the University of Alabama at Birmingham show how a low dose of cadmium produces deleterious stress in lung epithelial cells, and their results highlight potential therapeutic targets to explore in cadmium exposure and subsequent lung damage.

The research, led by Veena Antony, MD, professor in the UAB Department of Medicine, focuses on microRNA-381 and the expression of a chloride channel gene called ANO1 in lung tissue samples and epithelial cells. of the respiratory tract. ANO1 helps produce mucus in the airways; But overproduction of mucus in chronic lung disease can lead to thickening of the airways and blockage of mucus, thereby worsening the severity of the disease. Thus, overexpression of ANO1 may exacerbate COPD.

UAB researchers compared lung tissue samples from nine “never” smokers, who had no history of smoking, and lung tissue samples from 13 “never” smokers with COPD who had a history of smoking ranging from 15 to 25 pack-years per person. .

A pack-year is generally defined as smoking one pack of cigarettes per day for one year. The researchers found that “never” smokers, unlike “never” smokers, had upregulated ANO1 expression in airway epithelial cells.

Similarly, airway epithelial cells in bronchoalveolar lavage fluid from a non-COPD subject and a smoker with COPD showed greater ANO1 expression in cells from the COPD subject.

The researchers then tested the direct effect of very low doses of cadmium on normal human airway epithelial cells. These cells were grown on an air-liquid interface that allows airway cells to differentiate normally. Two weeks of exposure to 0.5 or 1.0 micromolar cadmium chloride in the liquid layer increased ANO1 expression 12- to 14-fold.

MicroRNAs have the ability to negatively regulate the expression of a gene by direct interaction with the mRNA sequence of that gene. The UAB team used computer software analysis to identify microRNA-381 as the microRNA with the most interaction with ANO1 mRNA, suggesting that microRNA-381 is a regulator ANO1 negative. Certain heavy metals are known to negatively regulate microRNAs.

Antony and colleagues used a synthetic microRNA-381 inhibitor to inhibit microRNA-381 expression in primary human airway epithelial cells from COPD subjects and found that ANO1 expression was upregulated.

In contrast, adding a microRNA-381 mimic – a synthetic RNA that acts like microRNA-381 to increase the amount of downregulation – to these cells decreased ANO1 expression. These results reinforced the UAB researchers’ premise that cadmium downregulates microRNA-381 expression to upregulate ANO1 expression in airway epithelial cells.

Finally, the researchers found that even when primary human airway epithelial cells from subjects with COPD were also exposed to 1 micromolar of cadmium chloride, the microRNA-381 inhibitor still upregulated ANO1 and the mimic upregulated always negatively ANO1.

“Our observations from experiments involving low-dose cadmium exposure of epithelial cells suggest that ANO1 is a direct target of miR-381, which is downregulated upon low-dose cadmium exposure,” Antony said.

“Thus, cigarette-induced cadmium toxicity may alter mechanisms of cellular homeostasis at very low concentrations, and cadmium exposure in a person with existing lung disease may have an additive or adverse effect with increased susceptibility to infections and environmental allergens.

“This interaction of cadmium, microRNA-381, and ANO1 suggests that microRNAs may act as potential therapeutic targets to be further explored in cases of cadmium exposure and subsequent lung injury.”