Pathophysiological background of the disease
COPD encompasses inflammatory diseases that cause structural
abnormalities to the airways and or pulmonary parenchyma [64],
usually caused by smoking or inhaled particulates [65]. Pronounced
ventilation-perfusion inequalities within poorly ventilated, yet
well-perfused alveoli, result in hypoxemia and, in certain patients,
hypercapnia [66]. As the disease progresses, inflammation-induced
hyperplasia of respiratory glands significantly increases the production
of viscoid mucus, leading to the obstruction of both smaller and larger
airways. Consequently, this obstruction culminates in hypoxia and
respiratory endothelial cell failure. Cough and dyspnea represent the
primary symptoms of this condition. Hypoxic respiratory endothelial
cells in COPD lungs exhibit an increased sodium absorption, attributed
to the upregulated expression of epithelial Na+ channels (ENaC),
consequently leading to mucus thickening [67]. Paradoxically, the
opposite effect has been observed in healthy individuals who developed
high altitude pulmonary edema. In these individuals, hypoxia reduced
transepithelial sodium transport mediated by ENaC, resulting in the
accumulation of fluid in the alveoli [68].
COPD is associated with systemic inflammation and numerous
comorbidities, most notably cardiovascular disease [69, 70]. Hypoxia
plays a vital role in this process because the increase in the HIF
cascade stimulates angiogenesis within atherosclerotic plaques [69].
There is a vicious cycle between the COPD-induced inflammation and
hypoxia where inflammation increases metabolic demand and hypoxia
increases the levels of reactive oxidative species, an inflammatory
agent. In mice, the combination of a high/fat diet and chronic
intermittent hypoxia has been shown to have a significant negative
impact on atherosclerosis [6]. However, the direct effect of hypoxia
in connecting COPD and atherosclerosis in the absence of associated
inflammation requires further investigation, which could be addressed
through laboratory-induced hypoxia studies.