Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels

Abstract

BackgroundThe Cystic Fibrosis Transmembrane conductance Regulator (CFTR) is a chloride channel that primarily resides in airway epithelial cells. Decreased CFTR expression and/or function lead to impaired airway surface liquid (ASL) volume homeostasis, resulting in accumulation of mucus, reduced clearance of bacteria, and chronic infection and inflammation.MethodsExpression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients with established GOLD stage 4. CFTR protein and mRNA were quantified by immunohistochemistry and quantitative RT-PCR, respectively. Metals present in lung samples were quantified by ICP-AES. The effect of cigarette smoke on down-regulation of CFTR expression and function was assessed using primary human airway epithelial cells. The role of leading metal(s) found in lung samples of GOLD 4 COPD patients involved in the alteration of CFTR was confirmed by exposing human bronchial epithelial cells 16HBE14o- to metal-depleted cigarette smoke extracts.ResultsWe found that CFTR expression is reduced in the lungs of GOLD 4 COPD patients, especially in bronchial epithelial cells. Assessment of metals present in lung samples revealed that cadmium and manganese were significantly higher in GOLD 4 COPD patients when compared to control smokers (GOLD 0). Primary human airway epithelial cells exposed to cigarette smoke resulted in decreased expression of CFTR protein and reduced airway surface liquid height. 16HBE14o-cells exposed to cigarette smoke also exhibited reduced levels of CFTR protein and mRNA. Removal and/or addition of metals to cigarette smoke extracts before exposure established their role in decrease of CFTR in airway epithelial cells.ConclusionsCFTR expression is reduced in the lungs of patients with severe COPD. This effect is associated with the accumulation of cadmium and manganese suggesting a role for these metals in the pathogenesis of COPD.

Cadmium in tobacco smokers: a neglected link to lung disease?

“…Taken together, the association of increased concentrations of cadmium in urine [29], blood [16] and lungs [17,18] with smoking, declining ventilatory lung function and the diagnosis of COPD, respectively, has been demonstrated in several studies (summarised in figure 1). However, the current body of evidence is insufficient to conclude whether urinary or blood cadmium concentrations accurately reflect the accumulation of cadmium in the lung.…”

“…In fact, the cadmium content was directly proportional to the total tobacco consumption ("tobacco load") among patients with GOLD stage IV (58±10.8 pack-years) and among those with GOLD stage 0 (22.5±12.1 pack-years). The fraction of accumulated cadmium in the lung tissue of GOLD stage IV patients was 0.0015-0.0032 µg·mg −1 dry weight tissue, whereas in the case of GOLD stage 0 patients, it was below the detection limit [17]. However, the investigation was limited to a relatively small number of subjects per study group (n=9-11).…”

“…It was reported that there was a higher accumulation of cadmium in human lung tissue obtained from the Lung Tissue Research Consortium (National Institutes of Health) among patients with very severe (Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV) compared to patients with very mild (GOLD stage 0) COPD [17]. In fact, the cadmium content was directly proportional to the total tobacco consumption ("tobacco load") among patients with GOLD stage IV (58±10.8 pack-years) and among those with GOLD stage 0 (22.5±12.1 pack-years).…”

Will chronic e-cigarette use cause lung disease?

“…Aldehydes and heavy metals have been shown to have a number of cytotoxic effects on epithelia, including adduct formation to DNA (32,140,154). Additionally, tobacco smoke, as well as aldehydes, cadmium, and oxidative stress, also affect plasma membrane proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR) (25,33,70,137), which is required for fluid secretion in the lung (35,60). In contrast, e-liquids (the flavored liquids that are heated to form the E-Cig vapor) are thought to be much simpler and ostensibly contain nicotine (ϳ6 -18 mg/ml) in a liquid vehicle (typically propylene glycol and/or glycerin), along with sweeteners and flavorings (65).…”

CFTR: A new horizon in the pathomechanism and treatment of pancreatitis

“…The interpretation of these results, at least with respect to the compounds responsible for the inhibitory effect of CFTR, is difficult as cigarette smoke is estimated to contain more than 7000 chemical components. Nevertheless, several constituents of cigarette smoke have been implicated in the inhibitory effects on CFTR such as acrolein [65], cadmium and manganese [67]. Moreover, these effects were ameliorated by the use of various antioxidants like N-acetylcysteine (a known scavenger of acrolein) or alphatocopherol, suggesting that free radical-induced damage may be responsible for the inhibition of CFTR by cigarette smoke [68].…”