Endotyping COPD: hypoxia-inducible factor-2 as a molecular “switch” between the vascular and airway phenotypes?

Abstract

COPD is a heterogeneous disease with multiple clinical phenotypes. COPD endotypes can be determined by different expressions of hypoxia-inducible factors (HIFs), which, in combination with individual susceptibility and environmental factors, may cause predominant airway or vascular changes in the lung. The pulmonary vascular phenotype is relatively rare among COPD patients and characterised by out-of-proportion pulmonary hypertension (PH) and low diffusing capacity of the lung for carbon monoxide, but only mild-to-moderate airway obstruction. Its histologic feature, severe remodelling of the small pulmonary arteries, can be mediated by HIF-2 overexpression in experimental PH models. HIF-2 is not only involved in the vascular remodelling but also in the parenchyma destruction. Endothelial cells from human emphysema lungs express reduced HIF-2α levels, and the deletion of pulmonary endothelialHif-2α leads to emphysema in mice. This means that both upregulation and downregulation of HIF-2 have adverse effects and that HIF-2 may represent a molecular “switch” between the development of the vascular and airway phenotypes in COPD. The mechanisms of HIF-2 dysregulation in the lung are only partly understood. HIF-2 levels may be controlled by NAD(P)H oxidasesviairon- and redox-dependent mechanisms. A better understanding of these mechanisms may lead to the development of new therapeutic targets.

Pulmonary Vasodilator Therapy in Severe Pulmonary Hypertension Due to Chronic Obstructive Pulmonary Disease (Severe PH-COPD): A Systematic Review and Meta-Analysis

“…This study also showed that HIF-2α overexpression was protective against the development of emphysema [48]. These observations lead to the hypothesis that HIF-2 transcription factors can control the genes that are involved in vascular remodeling and lung alveolar healing, which act as a molecular "switch", resulting in severe PH-COPD [13]. Further research is needed to define if HIF-2 augmentation or suppression can be used as therapeutic targets in severe COPD or pulmonary vascular phenotype, respectively.…”

“…Patients with severe PH-COPD may have predominantly circulatory limitations to their symptoms with signs of right ventricular failure and are phenotypically distinct from COPD without PH or mild PH. The hypoxia-inducible factor-2 is considered a possible molecular switch that may result in airway versus vascular remodeling [13].…”

Expression of HIF-1α in pediatric asthmatic patients

“…Given their involvement in these crucial physiological processes, HIFs could potentially serve as biomarkers for certain lung conditions. However, further research would be required to confirm this hypothesis [ 27 ].…”

A preclinical animal study to evaluate the operability and safety of domestic one-way endobronchial valves

“…The destruction of alveolar walls causes loss of elastic recoil, airway closure during exhalation, and air trapping in distal air spaces. Severe emphysema substantially affects patients' quality of life and is highly susceptible to a series of complications such as respiratory failure, which can be life-threatening (3). Most traditional interventions, such as oxygen inhalation combined with antispasmodic drugs and rehabilitation exercises, have minimal effects and fail to adequately control disease progression in patients with advanced emphysema (4)(5)(6)(7).…”