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

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Creator
  • Tarran, Robert
    • Affiliation: School of Medicine, Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center
  • Tyrrell, Jean
    • Affiliation: School of Medicine, Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center
  • Da Tan, Chong
    • Affiliation: School of Medicine, Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center
Abstract
  • Abstract 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.
Date of publication
DOI
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Resource type
  • Article
Rights statement
  • In Copyright
Rights holder
  • Fatemat Hassan et al.; licensee BioMed Central Ltd.
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Journal title
  • Respiratory Research
Journal volume
  • 15
Journal issue
  • 1
Page start
  • 69
Language
  • English
Is the article or chapter peer-reviewed?
  • Yes
ISSN
  • 1465-9921
Bibliographic citation
  • Respiratory Research. 2014 Jun 23;15(1):69
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  • Open Access
Publisher
  • BioMed Central Ltd
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