The effect of low-dose cadmium on airway epithelial cells in COPD cases by Jeff Hansen
Veena Anthony , M . D . Photography : Lexi Coon
Cigarette smoke exposure 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 that can be adsorbed onto microparticles in smoke that travel deep into the lungs . Furthermore , the body is not able to remove cadmium , which accumulates in longtime smokers .
In a Scientific Reports study , University of Alabama at Birmingham researchers show how a low dose of cadmium produces a deleterious stress in lung epithelial cells , and their findings highlight potential therapeutic targets to be explored in cadmium-exposure and subsequent lung injury .
The research , led by Veena Antony , M . D ., a 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 airway epithelial cells . ANO1 helps produce mucus in the airway ; but overproduction of mucus in chronic lung disease can lead to airway thickening and mucus blockage , adding to severity of the disease . Thus , overexpression of ANO1 can exacerbate COPD .
The UAB researchers compared lung tissue samples from nine ? never ? smokers , who had zero history of cigarette smoking , and lung tissue samples from 13 ? ever ? smokers with COPD who had a history of smoking that ranged from 15 to 25 pack years per person . One pack year is generally defined as smoking one pack of cigarettes a day for one year . The researchers found that ? ever ? smokers , in contrast to ? never ? smokers , had upregulated ANO1 expression in airway epithelial cells .
Similarly , airway epithelial cells in a bronchoalveolar lavage fluid from one non-COPD subject and one smoker with COPD showed greater ANO1 expression in the COPD-subject cells .
The researchers next 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 the airway cells to differentiate normally . Two weeks of exposure to 0.5 or 1.0 micromolar cadmium chloride in the liquid layer increased expression of ANO1 12 to 14 times .
MicroRNAs have the ability to downregulate expression of a gene by direct interaction with that gene ? s mRNA sequence . The UAB team used computer software analysis to identify microRNA-381 as the microRNA with most interaction with ANO1 mRNAs , suggesting that microRNA-381 is a negative regulator of ANO1 . Some heavy metals are known to negatively regulate microRNAs .
Antony and colleagues used a synthetic inhibitor for microRNA-381 to inhibit the expression of microRNA-381 in primary human airway epithelial cells from subjects with COPD , and found that ANO1 expression was upregulated significantly . In contrast , adding a microRNA-381-mimic ? a synthetic RNA that acts like microRNA-381 to increase the amount of negative regulation ? to those cells decreased ANO1 expression . These results strengthened the premise of the UAB researchers that cadmium negatively regulates microRNA-381 expression to upregulate ANO1 expression in airway epithelial cells .
Lastly , researchers found that , even when primary human airway epithelial cells from subjects with COPD were also exposed to 1 micromolar cadmium chloride , the microRNA-381 inhibitor still upregulated ANO1 and the mimic still downregulated ANO1 .
PULMONARY , ALLERGY , AND CRITICAL CARE MEDICINE