Circulating Progenitor Cells and Vascular Dysfunction in Chronic Obstructive Pulmonary Disease

<div><p>Background</p><p>In chronic obstructive pulmonary disease (COPD), decreased progenitor cells and impairment of systemic vascular function have been suggested to confer higher cardiovascular risk. The origin of these changes and their relationship with alterations in the pulmonary circulation are unknown.</p><p>Objectives</p><p>To investigate whether changes in the number of circulating hematopoietic progenitor cells are associated with pulmonary hypertension or changes in endothelial function.</p><p>Methods</p><p>62 COPD patients and 35 controls (18 non-smokers and 17 smokers) without cardiovascular risk factors other than cigarette smoking were studied. The number of circulating progenitors was measured as CD45⁺CD34⁺CD133⁺ labeled cells by flow cytometry. Endothelial function was assessed by flow-mediated dilation. Markers of inflammation and angiogenesis were also measured in all subjects.</p><p>Results</p><p>Compared with controls, the number of circulating progenitor cells was reduced in COPD patients. Progenitor cells did not differ between control smokers and non-smokers. COPD patients with pulmonary hypertension showed greater number of progenitor cells than those without pulmonary hypertension. Systemic endothelial function was worse in both control smokers and COPD patients. Interleukin-6, fibrinogen, high sensitivity C-reactive protein, vascular endothelial growth factor and tumor necrosis factor were increased in COPD. In COPD patients, the number of circulating progenitor cells was inversely related to the flow-mediated dilation of systemic arteries.</p><p>Conclusions</p><p>Pulmonary and systemic vascular impairment in COPD is associated with cigarette smoking but not with the reduced number of circulating hematopoietic progenitors. The latter appears to be a consequence of the disease itself not related to smoking habit.</p></div

Clinical characteristics, lung function, cardiovascular and laboratory measurements.

<p>Data are shown as mean ± SD.</p><p>Definition of abbreviations: COPD: Chronic obstructive pulmonary disease; FEV₁: post-bronchodilator forced expiratory volume in the first second; TLC: total lung capacity; RV: residual volume; DLco: diffusing capacity of the lung for carbon monoxide; PaO₂: partial pressure of arterial oxygen; PaCO₂: partial pressure of arterial carbon dioxide; HDL: high-density lipoprotein; LDL: low-density lipoprotein.</p><p>*P<0.05 compared with control nonsmokers.</p>†<p>P<0.05 compared with control smokers.</p>‡<p>The Framingham risk score can range from −6 to 19, with higher scores indicating greater cardiovascular risk.</p><p>Clinical characteristics, lung function, cardiovascular and laboratory measurements.</p

Vascular reactivity of the brachial artery in the study population.

<p>Data are shown as median (interquartile range).</p><p>*P<0.05 compared with control nonsmokers.</p><p>Vascular reactivity of the brachial artery in the study population.</p

Inverse correlation between progenitor cells and endothelial function.

<p>Inverse relationship between the number of circulating CD45+CD34+CD133+ progenitor cells and the endothelial function, assessed by flow-mediated dilation, of the brachial artery in patients with COPD (r = −0.27, P<0.05).</p

Number of circulating hematopoietic progenitors cells in nonsmokers, control smokers and COPD patients.

<p>(A) Number of CD45+CD34+ labelled cells, expressed as percent of lymphomonocytes. (B) Number of CD45+CD34+CD133+ labelled cells, expressed as percent of lymphomonocytes. The box represents the interquartile range. The solid line indicates the median and the dashed line indicates the mean. The whiskers extend from the box to the 90th and 10th percentiles. One-way analysis of variance and post hoc pairwise comparisons using the Dunn’s test.</p

Relationship between endothelial function, assessed by flow-mediated dilation, of the brachial artery and COPD severity.

<p>(A) Patients grouped according to trans-tricuspid systolic pressure gradient suggestive of pulmonary hypertension (>31 mmHg), assessed by Doppler echocardiography. (B) Patients grouped according to the spirometric GOLD stage. The box represents the interquartile range. The solid line indicates the median and the dashed line indicates the mean. The whiskers extend from the box to the 90th and 10th percentiles. One-way analysis of variance and post hoc pairwise comparisons using the Dunn’s test.</p

Relationship between the number of circulating CD45+CD34+CD133+ labelled cells and COPD severity.

<p>(A) Patients grouped according to the spirometric GOLD stage. (B) Patients grouped according to PaO₂ value above or below the median value (70 mmHg). (C) Patients grouped according to DLCO above or below the median value (60% predicted). (D) Patients grouped according to trans-tricuspid systolic pressure gradient suggestive of pulmonary hypertension (>31 mmHg), assessed by Doppler echocardiography. The box represents the interquartile range. The solid line indicates the median and the dashed line indicates the mean. The whiskers extend from the box to the 90th and 10th percentiles. One-way analysis of variance post hoc pairwise comparisons using the Kruskal-Wallis and the Dunn’s test.</p

Vascular and systemic inflammatory markers in the study population.

<p>Data are shown as median (interquartile range).</p><p>Definition of abbreviations: IL-6: Interleukin-6; VEGF: vascular endothelial growth factor; hsCRP: high sensitive C-reactive protein; BNP: Brain natriuretic peptide; TNF-α: tumour necrosis factor α.</p><p>*p<0.05 Chi-square.</p>†<p>P<0.05 compared with control nonsmokers.</p>‡<p>TNF-α was measured in 23 control subjects (13 nonsmokers and 10 smokers) and 30 COPD patients.</p><p>Vascular and systemic inflammatory markers in the study population.</p