Molecular Characteristics and Treatment of Endothelial Dysfunction in Patients with COPD: A Review Article

Abstract

Patients with chronic obstructive pulmonary disease (COPD) show systemic consequences, such as chronic systemic inflammation leading to changes in the airway, airway penetrability, and endothelial function. Endothelial dysfunction is characterized by a list of alterations of endothelium towards reduced vasodilation, proinflammatory state, detachment and apoptosis of endothelial cells, and development of atherosclerosis. COPD-induced endothelial dysfunction is associated with elevated cardiovascular risk. The increment of physical activities such as pulmonary rehabilitation (PR) training have a significant effect on COPD, thus, PR can be an integrative part of COPD treatment. In this narrative review the focus is on the function of endothelial inflammatory mediators [cytokines, chemokines, and cellular proteases] and pulmonary endothelial cells and endothelial dysfunction in COPD as well as the effects of dysfunction of the endothelium may play in COPD-related pulmonary hypertension. The relationship between smoking and endothelial dysfunction is also discussed. The connection between different pulmonary rehabilitation programs, arterial stiffness and pulse wave velocity (PWV) is presented. Endothelial dysfunction is a significant prognostic factor of COPD, which can be characterized by PWV. We discuss future considerations, like training programs, as an important part of the treatment that has a favorable impact on the endothelial function.

Keywords: COPD; cardiovascular risk; endothelial dysfunction; pulmonary hypertension; pulmonary rehabilitation.

Figure 1

Exposure to cigarette smoke and air pollution activates immune cells [e.g., macrophages, neutrophils] which drive reactive oxygen species production and systemic inflammation. The process finally promotes cardiovascular diseases (CVD) and progression, ultimately leading to CVD-associated death.

Figure 2

Schematic picture of healthy and COPD alveolar septum. In the COPD pulmonary tissue apoptotic pneumocytes appear in the alveolar wall and the wall becomes disrupted. The basement membrane of the pulmonary epithelium is fragmented. As the result of the enhanced enzyme activity the amount of elastic fibers is decreased. The pulmonary vasculature is thickened with arterial smooth muscle cells.

Figure 3

Classification of the most frequently listed markers during COPD.

Figure 4

Crosstalk of the pulmonary endothelium in COPD. Neutrophils migrate between endothelial cells and this process is called paracellular migration, while when it happens via one endothelial cell, it is called transendothelial migration (TEM). Macrophage-1 Antigen (MAC-1) is upregulated in neutrophils and MAC-1 binds to Endothelial Intracellular Adhesion Molecules-1 (ICAM-1). Serum level of ICAM-1 is associated with emphysema. Endothelial-Leukocyte Adhesion Molecule-1 (ELAM-1) is also involved in TEM and upregulated in the serum of COPD patients. As the result of decreased oxygen level in the pulmonary tissue Hypoxia Induced Factors (HIF) are activated and enhance the transcription of certain target genes, such as Platelet-Derived Growth Factor β (PDGFβ) which elevates the proliferation rate of arterial smooth muscle cells. These pulmonary endothelial cells also release endothelin-1 (ET-1) and araginase1–2 which are responsible for the vasoconstriction of the arterial smooth muscle cells. The endothelial apelin inhibits vasodilation. And VEGF produced by endothelial cells acts as an autocrine and paracrine factor via VEGF receptors (VEGFR) and promotes angiogenesis and enhances intercellular junctions.