Progenitor cell mobilisation and recruitment in pulmonary arteries in chronic obstructive pulmonary disease

Abstract

Background: Pulmonary vascular abnormalities are a characteristic feature of chronic obstructive pulmonary disease (COPD). Cigarette smoking is the most important risk factor for COPD. It is believed that its constant exposure triggers endothelial cell damage and vascular remodelling. Under pathological conditions, progenitor cells (PCs) are mobilized from the bone marrow and recruited to sites of vascular injury. The aim of the study was to investigate whether in COPD the number of circulating PCs is related to the presence of bone marrow-derived cells in pulmonary arteries and the association of these phenomena to both systemic and pulmonary endothelial dysfunction.

Methods: Thirty-nine subjects, 25 with COPD, undergoing pulmonary resection because of a localized carcinoma, were included. The number of circulating PCs was assessed by flow cytometry using a triple combination of antibodies against CD45, CD133 and CD34. Infiltrating CD45⁺ cells were identified by immunohistochemistry in pulmonary arteries. Endothelial function in systemic and pulmonary arteries was measured by flow-mediated dilation and adenosine diphosphate-induced vasodilation, respectively.

Results: COPD patients had reduced numbers of circulating PCs (p < 0.05) and increased numbers of CD45⁺ cells (< 0.05) in the pulmonary arterial wall than non-COPD subjects, being both findings inversely correlated (r = - 0.35, p < 0.05). In pulmonary arteries, the number of CD45⁺ cells correlated with the severity of vascular remodelling (r = 0.4, p = 0.01) and the endothelium-dependent vasodilation (r = - 0.3, p = 0.05). Systemic endothelial function was unrelated to the number of circulating PCs and changes in pulmonary vessels.

Conclusion: In COPD, the decrease of circulating PCs is associated with their recruitment in pulmonary arteries, which in turn is associated with endothelial dysfunction and vessel remodelling, suggesting a mechanistic link between these phenomena. Our findings are consistent with the notion of an imbalance between endothelial damage and repair capacity in the pathogenesis of pulmonary vascular abnormalities in COPD.

Keywords: COPD; DLco; Endothelial dysfunction; Progenitor cells; Vascular remodeling.

Fig. 1

Number of CD45⁺CD34⁺CD133⁺ and CD45⁺ cells in COPD. a Number of circulating CD34⁺CD133⁺CD45⁺ progenitor cells in non-COPD and COPD patients expressed as percent of lymphomonocytes; (b) Quantification of CD45⁺ infiltrates in the intima of the pulmonary arteries expressed as a number per mm of endothelium in non-COPD and COPD subjects, * P < 0.05, compared with non-COPD subjects, Mann Whitney test. Values expressed as mean ± SD; (c) Relationship between the number of CD45⁺cells and the number of circulating CD45⁺CD34⁺CD133⁺ cells; Spearman rank correlation test, Non-COPD (n = 13), COPD (n = 24), * P < 0.05

Fig. 2

Morphometric measurements in non-COPD and COPD subjects. a Percentage of artery wall thickness, % measured radius; (b) Percentage of lumen area, % total area; (c) Percentage of muscular area, % total area in non-COPD and COPD subjects. Non-COPD (n = 13), COPD (n = 23), * P < 0.05, ** P < 0.01compared with non-COPD subjects, Mann Whitney test. Values expressed as mean ± SD

Fig. 3

CD45⁺CD34⁺CD133⁺, CD45⁺ cells and the percentage of artery lumen. a Relationship between the number of CD45⁺CD34⁺CD133⁺ cells and the percentage of lumen area, % total area artery lumen of pulmonary arteries; (b) Relationship between the number of CD45⁺ cells and the percentage of lumen area, % total area artery lumen of pulmonary arteries. Non-COPD (n = 11), COPD (n = 21), Spearman rank correlation test, * P < 0.05

Fig. 4

CD34⁺CD133⁺CD45⁺, CD45⁺ cells and % of artery lumen and DLco levels. a Number of circulating CD34⁺CD133⁺CD45⁺progenitor cells in non-COPD and COPD patients grouped according to DLco above or below the median value (60% predicted); (b) Number of CD45⁺cells in non-COPD and COPD subjects grouped according to DLco above or below the median value (60% predicted); (c) % of artery lumen in non-COPD and COPD subjects grouped according to DLco above or below the median value (60% predicted). Non-COPD (n = 11), COPD (n = 21), * P < 0.05, Mann Whitney test. Values expressed as mean ± SD