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.