Chronic obstructive pulmonary disease (COPD) is one of the leading causes of morbidity and mortality worldwide, affecting the airways (i.e., chronic bronchitis and airway collapse), the parenchyma (i.e., hyperinflation, air trapping and emphysematous destruction) and the vasculature (i.e., hypoxic vasoconstriction, rarefaction and pulmonary arterial hypertension) with different severities Citation[1]. Pharmacotherapy for COPD is still under development to show disease-specific efficacy on disease progression and has a great need to explore new and effective therapeutic areas Citation[2,3].
Pathological angiogenesis has been suggested to be associated with the development and remodeling of COPD and tumor growth Citation[4]. COPD can result in both pulmonary and extrapulmonary vascular pathology, including endothelial barrier dysfunction, wall thickening, smooth muscular cell hypertrophy, inflammation and remodeling Citation[5]. The direct vascular changes and hyperinflation lead to the precapillary type of pulmonary hypertension, a fundamental alteration in the pulmonary vascular resistance.
Vascular pathology is a critical part of the structural tissue remodeling that occurs in COPD. However, the reason for the lack of effective treatment in COPD-associated vascular pathology is that the attention and understanding of such pathology remains limited and neglected Citation[6,7]. It has been proposed that endothelial dysfunction might be an initiating event, promoting vascular remodeling in COPD. The pathogenesis of vascular pathology in the development of COPD remains unclear, although a number of factors in COPD may involve atherosclerosis through vascular inflammation and oxidative stress Citation[8,9]. Therefore, we call for special attention from respiratory physicians and scientists to COPD-associated vascular pathology, in order to highlight clinical evidence of the pathology, explore potential mechanisms and biomarkers and propose a future therapeutic area for COPD.
Clinical evidence of COPD-associated vascular pathology
The pulmonary hypertension in chronic lung disease has been suggested to result from remodeling, rarefaction or angiogenesis Citation[10], associated with increased morbidity and mortality. Hypoxia, inflammation and increased shear stress can be the primary stimuli for remodeling and hyper-resistance of both pulmonary and extrapulmonary vessels, including intimal, medial and adventitial hypertrophy, which lead to encroachment into and reduction of the vascular lumen. In addition, the number of blood vessels may be reduced in the hypertensive lung, contributing to increased vascular resistance. It was found that 25–30% of hospitalized patients with exacerbations of COPD had deep-vein thrombosis. The initial evidence for COPD-associated vascular pathology was the entire avascular changes in alveolar septa in patients with emphysema, as assessed by pathological examination by Liebow in 1959. Angiogenesis is a prominent feature of tissue remodeling in COPD, including increased number and size of vessels in the airway mucosa – functionally abnormal vessels Citation[11].
It is difficult to diagnose vascular pathology in the early stage of the disease, until the appearance of nonspecific clinical symptoms, including dyspnea, exercise intolerance and fatigue. Later symptoms often lead to the incorrect consideration of cardiorespiratory diseases. COPD-associated vascular pathology might be related to chronic inflammatory processes, vascular growth factors and impairment of airflow obstruction. For example, local production of VEGF was implicated as a major driver of angiogenesis in the airway component of COPD, although, paradoxically, emphysema appears to be due to a lack of VEGF in the lung parenchyma.
Potential mechanisms
Endothelial cells
The endothelium of the pulmonary vasculature seems more sensitive to inflammatory stimuli than those of the systemic vasculature Citation[11]. Although both hypoxia and inflammation cause angiogenesis in extrapulmonary organs, remodeling and resistance of vessels is rarely observed. Chronic airway inflammation can lead to pulmonary vascular remodeling with or without hypertension. It is possible that smoking or hypoxia might induce alterations of adhesion molecule expression on endothelial surfaces and activate endothelial cells to produce a number of inflammatory mediators, contributing to the systemic vascular pathology in COPD. Conversely, inflammatory mediators produced from the lungs during the chronic process may initiate the dysfunction of the endothelial barrier in the systemic circulation.
Inflammation
Chronic inflammation is one of the most important factors responsible for the development of COPD-associated vascular pathology. Inflammatory cells, such as neutrophils, macrophages and monocytes, have been considered the key players in the development of COPD. Inflammatory mediators generated from either inflammatory or structural cells, such as epithelial and smooth muscle cells, may act as the interorgan messenger to carry pulmonary inflammation to extrapulmonary organs, as proposed in other diseases Citation[12]. It has been found that inflammation and angiogenesis were associated, linked and often temporally overlapped in COPD Citation[13].
Protease/antiprotease imbalance
Protease/antiprotease imbalance has been proposed to be responsible for the pathogenesis of emphysema, evidenced by the potential that protease inhibitors may prevent emphysema Citation[14]. Cigarette smoke-associated inflammation and oxidative stress may induce expression and activation of matrix metalloproteinases (MMPs), which were considered to be related to the formation of smoking-related vascular disease Citation[15,16]. MMPs may also participate in cigarette smoke-induced pulmonary vascular remodeling and emphysema through cadmium. Cadmium could induce lung proteolysis through increased activation of MMP-2 and MMP-9. Cadmium content of the infrarenal aorta increased with increased incidence and period of cigarette smoke exposures.
Others
The platelet has been found to play an important role in the pathogenesis of inflammatory diseases in COPD Citation[17,18]. Overproduction of oxygen free radicals may be involved in the exacerbation of COPD. The CXC chemokine family, in which the first two cysteines are separated by a single amino acid, is a pleiotropic family of cytokines that are involved in promoting the trafficking of various leukocytes and regulating angiogenesis and vascular remodeling. The CXC chemokine family is unique in regulating vascular remodeling.
Considerations on future studies
Biomarkers
It is important to select disease-specific biomarkers to indicate the specificity, severity, duration, diagnosis and progress of COPD-associated vascular pathology Citation[19]. Proteomic technology has been applied for screening biomarkers. An increasing number of studies on the application of cellular proteomics have appeared in studies mapping protein profiles of inflammatory cells (e.g., leukocytes) and structure cells (e.g., epithelia), helping to contribute to the understanding of potential mechanisms involved in cell function. Future studies using proteomic technology should investigate molecular mechanisms of COPD-associated vascular pathology, identify disease-related biomarkers and validate therapeutic effects. It is important to explore the relationships between advanced proteomic biotechnology, clinical proteomics, tissue imaging and profiling and COPD-associated vascular pathology in order to improve the clinical outcomes of these patients. This technology allows the identification of biomarkers for COPD-associated vascular pathology.
In vivo molecular investigation
The different aspects of COPD can be addressed using a combination of morphological and functional techniques. Nuclear magnetic resonance (NMR) is a technique for morphological imaging of the lung parenchyma and airways. Identified proteins and metabolites can be assessed by tracer-based molecular imaging using MRI/spectroscopical imaging and PET. It is important to assess COPD-associated vascular pathology by tracing the target-labeling molecules under NMR. Such technology allows monitoring of dynamic alterations of COPD-associated vascular pathology in both pulmonary and extrapulmonary areas Citation[20].
Targeting therapies
Combination therapy of drugs relating to different mechanisms of action in order to maximize clinical benefit is one emerging therapeutic option in COPD-associated vascular pathology Citation[21–24]. To develop target-specific therapy is another alternative. A number of targets should be considered, such as muscarinic receptor, β-receptor, phosphodiesterase, TNF-α, granulocyte–macrophage colony-stimulating factor, chemokine receptor, p38 MAPK, phosphatidylinositol 3-kinase and NF-κB. There is reason to believe that multiple factors may be involved in the development of COPD-associated vascular pathology and that a combination of target-specific therapies will be of optimum benefit to patients.
In conclusion, COPD is a systemic inflammatory disease, originated from the lungs, with both pulmonary and extrapulmonary vascular pathology. COPD-associated vascular pathology is one of a number of critical factors responsible for the development of COPD-associated multiple organ dysfunction. A number of potential factors are involved in the pathogenesis of the disease. COPD-associated vascular pathology has the potential to be a new therapeutic area that improves patient outcomes. There is a great need to develop disease-specific biomarkers, molecular monitoring system and target-specific therapies in the future.
Financial & competing interests disclosure
The authors acknowledge research support from China Postdoctoral Science Foundation (NO 20070420596) and Shanghai Leading Academic Discipline Project (project number: B115). The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
No writing assistance was utilized in the production of this manuscript.
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