Multidrug resistance-associated protein-1 (MRP1) genetic variants, MRP1 protein levels and severity of COPD

<p>Abstract</p> <p>Background</p> <p>Multidrug resistance-associated protein-1 (MRP1) protects against oxidative stress and toxic compounds generated by cigarette smoking, which is the main risk factor for chronic obstructive pulmonary disease (COPD). We have previously shown that single nucleotide polymorphisms (SNPs) in <it>MRP1 </it>significantly associate with level of FEV₁in two independent population based cohorts. The aim of our study was to assess the associations of <it>MRP1 </it>SNPs with FEV₁level, MRP1 protein levels and inflammatory markers in bronchial biopsies and sputum of COPD patients.</p> <p>Methods</p> <p>Five SNPs (rs212093, rs4148382, rs504348, rs4781699, rs35621) in <it>MRP1 </it>were genotyped in 110 COPD patients. The effects of <it>MRP1 </it>SNPs were analyzed using linear regression models.</p> <p>Results</p> <p>One SNP, rs212093 was significantly associated with a higher FEV₁level and less airway wall inflammation. Another SNP, rs4148382 was significantly associated with a lower FEV₁level, higher number of inflammatory cells in induced sputum and with a higher MRP1 protein level in bronchial biopsies.</p> <p>Conclusions</p> <p>This is the first study linking <it>MRP1 </it>SNPs with lung function and inflammatory markers in COPD patients, suggesting a role of <it>MRP1 </it>SNPs in the severity of COPD in addition to their association with MRP1 protein level in bronchial biopsies.</p

Patient characteristics at baseline.

<p>Patient characteristics for current smokers and ex-smokers with COPD and groups treated with placebo and fluticasone (only compliant patients). Bronchial biopsies were available at baseline of 64 (elastic fibers), 56 (versican), 61 (decorin), 61 (collagen I) and 64 (collagen III) patients. After 30 months, bronchial biopsies of 32 compliant patients were available, tissue from 29 (elastic fibers), 26 (versican), 27 (decorin), 28 (collagen I) and 28 (collagen III) patients had sufficient surface area for analysis (≥0.09 mm²) (fluticasone and placebo groups combined). Data are presented as mean (SD) or median (IQR), unless otherwise stated. Methacholine PC₂₀: provocative concentration of methacholine that causes a 20% decrease in FEV₁, expressed as mean doubling doses. Part of the data have been published previously <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063430#pone.0063430-Lapperre1" target="_blank">[17]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063430#pone.0063430-Lapperre2" target="_blank">[22]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0063430#pone.0063430-Kunz1" target="_blank">[27]</a>.</p>*<p>p<0.05 compared to current smokers (two tailed unpaired t-tests).</p

Percentage and density of stained area at baseline of ex-smokers and smokers with COPD.

<p>Percentage (upper panel) and density (lower panel) of stained area in bronchial biopsies is presented. Ex-smokers are presented as open circles, current smokers as closed circles. Horizontal bars represent medians. No significant differences were found for all studied extracellular matrix proteins (both percentage stained area and density).</p

Inhaled Steroids Modulate Extracellular Matrix Composition in Bronchial Biopsies of COPD Patients:A Randomized, Controlled Trial

<p>Rationale: Smoking and inflammation contribute to the pathogenesis of chronic obstructive pulmonary disease (COPD), which involves changes in extracellular matrix. This is thought to contribute to airway remodeling and airflow obstruction. We have previously observed that long-term treatment with inhaled corticosteroids can not only reduce bronchial inflammation, but can also attenuate lung function decline in moderate-severe COPD. We hypothesized that inhaled corticosteroids and current smoking modulate bronchial extracellular matrix components in COPD.</p><p>Objective: To compare major extracellular matrix components (elastic fibers; proteoglycans [versican, decorin]; collagens type I and III) in bronchial biopsies 1) after 30-months inhaled steroids treatment or placebo; and 2) between current and exsmokers with COPD.</p><p>Methods: We included 64 moderate-severe, steroid-naive COPD patients (24/40 (ex)-smokers, 62 +/- 7 years, 46 (31-54) packyears, post-bronchodilator forced expiratory volume in one second (FEV1) 62 +/- 9% predicted) at baseline in this randomized, controlled trial. 19 and 13 patients received 30-months treatment with fluticasone or placebo, respectively. Bronchial biopsies collected at baseline and after 30 months were studied using (immuno) histochemistry to evaluate extracellular matrix content. Percentage and density of stained area were calculated by digital image analysis.</p><p>Results: 30-Months inhaled steroids increased the percentage stained area of versican (9.6% [CI 0.9 to 18.3%]; p = 0.03) and collagen III (20.6% [CI 3.8 to 37.4%]; p = 0.02) compared to placebo. Increased collagen I staining density correlated with increased post-bronchodilator FEV1 after inhaled steroids treatment (Rs = 0.45, p = 0.04). There were no differences between smokers and ex-smokers with COPD in percentages and densities for all extracellular matrix proteins.</p><p>Conclusions: These data show that long-term inhaled corticosteroids treatment partially changes the composition of extracellular matrix in moderate-severe COPD. This is associated with increased lung function, suggesting that long-term inhaled steroids modulate airway remodeling thereby potentially preventing airway collapse in COPD. Smoking status is not associated with bronchial extracellular matrix proteins.</p>

Relapse in FEV1 Decline After Steroid Withdrawal in COPD

BACKGROUND: We previously observed that 30 months of inhaled corticosteroid (ICS) treatment can attenuate FEV1 decline in COPD, but it is unclear whether withdrawal induces a relapse. We hypothesized that FEV1 decline, airway hyperresponsiveness (AHR), and quality of life (QOL) deteriorate after ICS cessation even after prolonged use. METHODS: One hundred fourteen patients with moderate to severe COPD finished randomized 6-month or 30-month treatment with fluticasone (500 mu g bid), 30-month treatment with fluticasone and salmeterol (500/50 mu g bid), or placebo (first part of the Groningen and Leiden Universities Corticosteroids in Obstructive Lung Disease [GLUCOLD] study [GL1]). The subsequent 5 years, patients were prospectively followed annually, treated by their physician (GLUCOLD follow-up study [GL2]). Postbronchodilator FEV1, AHR, and QOL were initially recorded at baseline, at 30 months (GL1), and annually during GL2. Analysis was performed by linear mixed-effects models. RESULTS: Among 101 adherent patients during GL1, 79 patients started and 58 completed GL2. Patients using ICSs during GL1, but only using ICSs 0% to 50% of the time during GL2 (n = 56 of 79), had significantly accelerated annual FEV1 decline compared with GL1 (difference GL2-GL1 [95% CI]: 30-month treatment with fluticasone and salmeterol, -68 mL/y [-112 to -25], P = .002; 30-month treatment with fluticasone, -73 mL/y [-119 to -26], P = .002), accompanied by deterioration in AHR and QOL. CONCLUSIONS: ICS discontinuation aft er 30 months in COPD can worsen lung function decline, AHR, and QOL during 5-year follow-up. This suggests that ICS treatment lacks sustained disease-modifying effect after treatment cessation