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

Fatemat Hassan, Xiaohua Xu, Gerard Nuovo, David W. Killilea, Jean Tyrrell, Chong Da Tan, Robert Tarran, Philip Diaz, Junbae Jee, Daren L Knoell, Prosper N. Boyaka, Estelle Cormet-Boyaka

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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.

Original languageEnglish (US)
Article number69
JournalRespiratory Research
Volume15
Issue number1
DOIs
StatePublished - Jun 23 2014

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Cystic Fibrosis Transmembrane Conductance Regulator
Chronic Obstructive Pulmonary Disease
Metals
Lung
Smoke
Tobacco Products
Epithelial Cells
Manganese
Cadmium
Messenger RNA
Chloride Channels
Proteins
Mucus
Homeostasis
Down-Regulation
Immunohistochemistry

Keywords

  • CFTR
  • COPD
  • Cadmium
  • Cigarette smoke
  • Lung epithelial cells
  • Manganese

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine

Cite this

Hassan, F., Xu, X., Nuovo, G., Killilea, D. W., Tyrrell, J., Da Tan, C., ... Cormet-Boyaka, E. (2014). Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. Respiratory Research, 15(1), [69]. https://doi.org/10.1186/1465-9921-15-69

Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. / Hassan, Fatemat; Xu, Xiaohua; Nuovo, Gerard; Killilea, David W.; Tyrrell, Jean; Da Tan, Chong; Tarran, Robert; Diaz, Philip; Jee, Junbae; Knoell, Daren L; Boyaka, Prosper N.; Cormet-Boyaka, Estelle.

In: Respiratory Research, Vol. 15, No. 1, 69, 23.06.2014.

Research output: Contribution to journalArticle

Hassan, F, Xu, X, Nuovo, G, Killilea, DW, Tyrrell, J, Da Tan, C, Tarran, R, Diaz, P, Jee, J, Knoell, DL, Boyaka, PN & Cormet-Boyaka, E 2014, 'Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels', Respiratory Research, vol. 15, no. 1, 69. https://doi.org/10.1186/1465-9921-15-69
Hassan, Fatemat ; Xu, Xiaohua ; Nuovo, Gerard ; Killilea, David W. ; Tyrrell, Jean ; Da Tan, Chong ; Tarran, Robert ; Diaz, Philip ; Jee, Junbae ; Knoell, Daren L ; Boyaka, Prosper N. ; Cormet-Boyaka, Estelle. / Accumulation of metals in GOLD4 COPD lungs is associated with decreased CFTR levels. In: Respiratory Research. 2014 ; Vol. 15, No. 1.
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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.",
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AU - Hassan, Fatemat

AU - Xu, Xiaohua

AU - Nuovo, Gerard

AU - Killilea, David W.

AU - Tyrrell, Jean

AU - Da Tan, Chong

AU - Tarran, Robert

AU - Diaz, Philip

AU - Jee, Junbae

AU - Knoell, Daren L

AU - Boyaka, Prosper N.

AU - Cormet-Boyaka, Estelle

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N2 - 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.

AB - 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.

KW - CFTR

KW - COPD

KW - Cadmium

KW - Cigarette smoke

KW - Lung epithelial cells

KW - Manganese

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