Cadmium Regulates the Expression of the CFTR Chloride Channel in Human Airway Epithelial Cells

Abstract

Cadmium is a toxic heavy metal ranked seventh on the Priority List of Hazardous Substances. As a byproduct of smelters, cadmium is a prevalent environmental contaminant. It is also a major component of cigarette smoke, and its inhalation is associated with decreased pulmonary function, lung cancer, and chronic obstructive pulmonary disease. Ion channels, including the cystic fibrosis transmembrane conductance regulator (CFTR), play a central role in maintaining fluid homeostasis and lung functions. CFTR is mostly expressed in epithelial cells, and little is known about the effect of cadmium exposure on lung epithelial cell function. We show that exposure to cadmium decreases the expression of the CFTR protein and subsequent chloride transport in human airway epithelial cells in vitro. Impairment of CFTR protein expression was also observed in vivo in the lung of mice after intranasal instillation of cadmium. We established that the inhibitory effect of cadmium was not a nonspecific effect of heavy metals, as nickel had no effect on CFTR protein levels. Finally, we show that selected antioxidants, including alpha-tocopherol (vitamin E), but not N-acetylcysteine, can prevent the cadmium-induced suppression of CFTR. In summary, we have identified cadmium as a regulator of the CFTR chloride channel present in lung epithelial cells. Future strategies to prevent the deleterious effect of cadmium on epithelial cells and lung functions may benefit from the finding that alpha-tocopherol protects CFTR expression and function.

Acute Effects of Cigarette Smoke Extract on Alveolar Epithelial Sodium Channel Activity and Lung Fluid Clearance

“…It has been shown that CSE inhibits chloride secretion in human bronchial epithelial cells (9,27,28) and induces CFTR internalization to promote airway surface liquid dehydration (8). The aforementioned studies, together with our current observation that CSE activates ENaC activity in an ROS-dependent manner, argue for a causal connection for CFTR regulation of lung ENaC, an area of molecular research that has been widely investigated (see Ref.…”

Cigarette Smoke Induces Systemic Defects in Cystic Fibrosis Transmembrane Conductance Regulator Function

“…Oxidative stress (41), cadmium (42), hypoxia (43), and the unfolded protein response (44) have each been associated with CFTR dysfunction and are potential contributors to the acquired phenotype, particularly in the lung, where exposures to these stimuli would be expected to be particularly prominent.…”

Emerging role of cystic fibrosis transmembrane conductance regulator as an epigenetic regulator: linking environmental cues to microRNAs

“…129 Exposure to cadmium, a major component of CS, was found to decrease the expression of CFTR in vitro and in vivo. 130 Interestingly, studies have also shown that CS exposure can alter miRNA profiles in humans and animals. 131,132 Notably, Hassan et al reported that miR-101 was highly upregulated by CS exposure, which has also been shown to directly target the CFTR 3 0 untranslated region, and suppressed CFTR expression in airway cells, 133 suggesting that miR-101 may mediate the CS-suppressed CFTR expression.…”