Hypoxia and reoxygenation: from basic science to bedside

A condition with inadequate oxygen supply to the tissues, hypoxia is important in the pathology of many human diseases, including cyanotic congenital heart defects, myocardial infarction, stroke, cancer, diabetes, aging, and pulmonary obstructive diseases. Most of the cell responses to hypoxia are regulated by the modulation of the hypoxia-inducible factors (HIFs), DNA-binding transcription factors that mediate adaptation to hypoxia through transcriptional activation of a multitude of genes encoding proteins needed to improve tissue oxygen delivery, energy metabolism, efficient management of hypoxia-induced toxic stress and regulation of processes as apoptosis, autophagy and cell cycle. However, the reoxygenation that often follows tissue hypoxia induces a massive burst of reactive oxygen species, which not only cause the oxidative damage central in the pathophysiology of hypoxia/reoxygenation injury, but also activate signaling mechanisms that in part synergize and in part oppose those induced by hypoxia. Consequently, it becomes often difficult to distinguish what is attributable to hypoxia and what is attributable to the reoxygenation that follows hypoxia. Although the deleterious consequences of hypoxia/reoxygenation originate from both the hypoxic and the reoxygenation processes, the new frontier of basic research may foster clues to understand the underlying mechanisms and to identify appropriate targets to design interventions aimed at reducing the toll of hypoxia/reoxygenation injury in several diseases.

One example is paradigmatic. For many years, hypoxia was considered to be associated with cardio-protection and to induce myocardial tolerance to ischemia/reperfusion. However, it is not hypoxia, but rather the reoxygenation after hypoxia, the real factor providing cardio-protection. Indeed, when exposed to chronic systemic hypoxia, hearts exhibit deleterious alterations in several signaling paths, including K+ATP channels, oxidative stress and mitogen-activated protein kinases.

Such changes are followed by right ventricular hypertrophy and impaired ability to recover from ischemia/reperfusion. These findings are corroborated by the clinical observation that the outcome of surgery for repair cyanotic congenital heart defects is complicated by myocardial damage due to re-oxygenation at the moment of the institution of cardiopulmonary bypass with elevated oxygen content, followed by ischemia/reperfusion injury when heart is arrested to perform the intra-cardiac repair. The protection afforded by intermittent hypoxia (but not by obstructive sleep apnea syndromes) further supports the view that appropriate management of hypoxia and reoxygenation may help curing many diseases and may provide pediatric surgeons valuable tools to reduce hypoxia-induced complicacies.

The purpose of this "Research Topic", attracting articles dealing with separate causes and effects of hypoxia and reoxygenation, aims at better understanding the pathophysiology and the mechanism of the hypoxia/reoxygenation injury in the cardiopulmonary system to improve the outcome of clinical management in patients affected by acute or chronic hypoxia. The leading topics are:

• Role of HIFs and other cell mechanisms during hypoxia and reoxygenation;
• Inducement of pulmonary hypertension and right heart failure by hypoxia and reoxygenation;
• Differential pathogenesis of intermittent hypoxia and obstructive sleep apnea syndromes;
• Roles of apoptosis and autophagy during hypoxia and reoxygenation.