Hyperoxia and surfactant dysfunction in critical illness: insights and future therapeutic prospects

Supplemental oxygen is an essential therapy during critical illness. However, patients with severe hypoxemic respiratory failure and/or acute respiratory distress syndrome often require high oxygen concentrations, exposing lungs to alveolar hyperoxia despite systemic hypoxemia, with consequent pulmonary oxygen toxicity. Pulmonary oxygen toxicity causes disruption of surfactant, which is essential for maintenance of alveolar functional anatomy, as well as efficient and effective gas exchange and immune regulation. This surfactant dysregulation can increase alveolar surface tension, causing alveolar collapse with atelectasis, resulting in poor lung compliance and impaired gas exchange. Hyperoxia-induced lung injury mechanisms may interact with mechanisms of harm associated with infections and mechanical ventilation. The intricate relationship between these different, interrelated stressors and altered surfactant metabolism and function is not yet delineated, particularly in humans. This review examines the current understanding of hyperoxia-induced surfactant dysregulation. We discuss potential mechanisms, including biochemical/compositional and functional changes to lipids and proteins including surfactant proteins A and D, epithelial atrophy, impaired surfactant synthesis/metabolism, redox imbalances, phospholipase A2, and altered macrophage clearance. Key areas for future research are outlined, emphasizing the need for clinically relevant human models that discriminate between the effects of oxygen therapy dose and duration, as well as other iatrogenic effects and underlying disease processes. We propose a roadmap to progress current knowledge and outline opportunities for well-designed human studies, novel surfactant preparations resistant to functional inhibition and breakdown, and technological developments, with the potential for leveraging these to identify innovative biomarkers, individualized therapeutic targets, and novel therapies in the future.