Characterization of pulmonary vascular remodelling in smokers and patients with mild COPD

Abstract

Intimal enlargement of pulmonary arteries is an early change in chronic obstructive pulmonary disease (COPD). The cellular and extracellular components that are involved in this enlargement are unknown. The present study was designed to characterize the structural changes occurring in pulmonary muscular arteries in the initial disease stages.Lung specimens from patients with moderate COPD (n=8; forced expiratory volume in one second (FEV1), 66¡10% predicted) and smokers without airflow obstruction (n=7; FEV1, 86¡6% pred), were investigated by histochemistry to characterize extracellular matrix proteins and by immunohistochemistry to identify intrinsic cells of the vascular wall.In both COPD patients and smokers, the majority of cells present in the enlarged intimas were stained by specific smooth muscle cell (SMC) markers. No staining with endothelial or fibroblast markers was shown. A proportion of SMCs did not stain with desmin, suggesting cellular heterogeneity in this population. Elastin was the most abundant extracellular matrix protein and collagen was seen in a lower proportion. The amount of collagen was related to the intimal thickness (pv0.001).The findings demonstrated smooth muscle cell proliferation, as well as elastin and collagen deposition, in the thickened intimas of pulmonary arteries in moderate chronic obstructive pulmonary disease patients and smokers, suggesting that these abnormalities may originate at an early stage in cigarette smoke-induced respiratory disease.

Pulmonary vascular changes in asthma and COPD

“…This switch is important during resolution of vascular injury and homeostasis and appears to be regulated by different miRNAs [38,39]. Chronic inflammation and tissue hypoxia are thought to induce increased vascular growth by directly effecting the VSM cells [40] the result being muscularisation and thickening of the blood vessels [13,40,41]. Factors such as tissue damage and sheer force also prompt both EPCs and endothelial cells to transdifferentiate into VSM cells [42,43].…”

“…Factors such as tissue damage and sheer force also prompt both EPCs and endothelial cells to transdifferentiate into VSM cells [42,43]. Blood vessels of the pulmonary system are generally quite lacking in VSM at all levels of the tracheobronchial tree, however thickened bronchial vessels are reported in patients with COPD, thought to result from alveolar hypoxia [13,40]. Increased vessel muscularisation is thought to lead to increased inflammatory infiltration into the localised tissue [13,40].…”

“…Blood vessels of the pulmonary system are generally quite lacking in VSM at all levels of the tracheobronchial tree, however thickened bronchial vessels are reported in patients with COPD, thought to result from alveolar hypoxia [13,40]. Increased vessel muscularisation is thought to lead to increased inflammatory infiltration into the localised tissue [13,40]. Cellular involvement of the vascular system is very complex, with multiple cell types being a significant source of angioregulatory mediators and the system is tightly regulated by the balance of pro-and anti-angiogenic stimuli in the environment.…”

“…Based on a number of clinical research studies and animal models, VEGF is the principal mediator implicated in lung neovascularisation and a potent pro-angiogenic growth factor that plays a key role in vascular remodelling both in normal and pathological conditions [13,47,48]. VEGF is a multifunctional cytokine and the VEGF family includes VEGF-A, VEGF-B, VEGF-C and VEGF-D. VEGF can induce vascular leakage, vessel permeability and angiogenesis [49].…”

“…Thereafter, a number of studies reported the involvement of specific growth factors, such as fibroblast growth factor (FGF), transforming growth factor (TGF) β1 and vascular endothelial growth factor (VEGF), during vascular remodelling in asthma and COPD [9][10][11][12]. Vascular remodelling, including thickening of the intimal and medial layers due to vascular smooth muscle (VSM) cell hypertrophy, is reported to progressively decline lung function [10,13] and vascular alterations in the pulmonary circulation may impair gas exchange in the alveolar compartments that result in pulmonary hypertension in some COPD patients [14]. Previous research has focused on the …”