Dataset Information

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

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.

SUBMITTER: Hassan F

PROVIDER: S-EPMC4106203 | biostudies-literature | 2014 Jun

REPOSITORIES: biostudies-literature

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Publications

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

Hassan Fatemat F Xu Xiaohua X Nuovo Gerard G Killilea David W DW Tyrrell Jean J Da Tan Chong C Tarran Robert R Diaz Philip P Jee Junbae J Knoell Daren D Boyaka Prosper N PN Cormet-Boyaka Estelle E

Respiratory research 20140623

<h4>Background</h4>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.<h4>Methods</h4>Expression of CFTR and the cigarette smoke metal content were assessed in lung samples of controls and COPD patients ...[more]

PMID: 24957904

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Project description:BACKGROUND:The class III NAD-dependent histone deacetylase (HDAC) sirtuin 1 (SIRT1) is an important regulator of senescence, aging, and inflammation. SIRT1de-acetylates chromatin histones, thereby silencing inflammatory gene transcription. We have reported increased steroid-resistant senescent pro-inflammatory CD28nullCD8+ T cells in patients with chronic obstructive pulmonary disease (COPD). We hypothesized that SIRT1 is reduced in these cells in COPD, and that treatment with SIRT1 activators (resveratrol, curcumin) and agents preventing NAD depletion (theophylline) would upregulate SIRT1 and reduce pro-inflammatory cytokine expression in these steroid-resistant cells. METHODS:Blood was collected from n?=?10 COPD and n?=?10 aged-matched controls. Expression of CD28, SIRT1, and pro-inflammatory cytokines was determined in CD8+ and CD8- T and natural killer T (NKT)-like cells cultured in the presence of ±1?µM prednisolone, ±5?mg/L theophylline, ±1?µM curcumin, ±25?µM resveratrol, using flow cytometry and immunofluorescence. RESULTS:There was an increase in the percentage of CD28nullCD8+ T and NKT-like cells in COPD patients compared with controls. Decreased SIRT1 expression was identified in CD28nullCD8+T and NKT-like cells compared with CD28+ counterparts from both patients and controls (e.g. CD28null 11?±?3% versus CD28+ 57?±?9%). Loss of SIRT1 was associated with increased production of IFN? and TNF?, steroid resistance, and disease severity. SIRT1 expression was upregulated in the presence of all drugs and was associated with a decrease in steroid resistance and IFN? and TNF? production by CD28nullCD8+T and NKT-like cells. The presence of the SIRT1 inhibitor, EX-527 negated [by 92?±?12% (median?±?SEM)] the effect of the SIRT1 activator SRT720 on the percentage of CD8+ T cells producing IFN? and TNF?. CONCLUSIONS:Steroid resistance in pro-inflammatory CD28nullCD8+ T and NKT-like cells is associated with decreased SIRT1 expression. Treatment with prednisolone, in combination with theophylline, curcumin or resveratrol increases SIRT1 expression, restores steroid sensitivity, and inhibits pro-inflammatory cytokine production from these cells and may reduce systemic inflammation in COPD. The reviews of this paper are available via the supplemental material section.

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

Similar Datasets

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