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

BACKGROUND: The 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. METHODS: Expression 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. RESULTS: We 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. CONCLUSIONS: CFTR 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.

Does epithelial sodium channel hyperactivity contribute to cystic fibrosis lung disease?

Airway epithelia absorb Na+ through the epithelial Na+ channel (ENaC) and secrete Cl- through the cystic fibrosis transmembrane conductance regulator (CFTR) anion channel. This balance maintains sufficient airway surface liquid hydration to permit efficient mucus clearance, which is needed to maintain sterility of the lung. Cystic fibrosis (CF) is a common autosomal recessive inherited disease caused by mutations in the CFTR gene that lead to the reduction or elimination of the CFTR protein. CF is a multi-organ disease that affects epithelia lining the intestines, lungs, pancreas, sweat ducts and vas deferens, among others. CF lungs are characterized by viscous, dehydrated mucus, persistent neutrophilia and chronic infections. ENaC is negatively regulated by CFTR and, in patients with CF, the absence of CFTR results in a double hit of reduced Cl-/HCO3- and H2O secretion as well as ENaC hyperactivity and increased Na+ and H2O absorption. Together, these effects are hypothesized to trigger mucus dehydration, resulting in a failure to clear mucus. Rehydrating CF mucus has become a recent clinical focus and yields important end-points for clinical trials. However, while ENaC hyperactivity in CF airways has been detected in vivo and in vitro, recent data have brought the role of ENaC in CF lung disease pathogenesis into question. This review will focus on our current understanding of the contribution of ENaC to CF pathogenesis.