Investigating the impact of oxygen on neutrophil biomechanics: targeting a new mechanism in acute lung injury
Year of award: 2024
Grantholders
Dr Katharine Lodge
Imperial College London, United Kingdom
Project summary
The remarkable capability of healthy neutrophils to deform as they traffic through narrow pulmonary capillaries ensures their rapid transit through the lung. During inflammation, cytoskeletal reorganization causes neutrophils to become less deformable (stiff), leading to entrapment in the lung microvasculature. Using Real-Time Deformability Cytometry (RT-DC), a novel microfluidic technique that measures cellular biomechanical profiles, I have shown that oxygen availability rapidly modulates the neutrophil cytoskeleton. At venous oxygen tension (5% O2), neutrophils are softest, aiding their transit through the extensive lung capillary network. During acute respiratory distress syndrome, patients experience systemic hypoxia (due to impaired gas transfer in inflamed lung) and hyperoxia (due to oxygen supplementation). In severe respiratory failure, patients receiving extracorporeal membrane oxygenation are exposed to further extremes of pathological hypoxia/hyperoxia. I have shown that neutrophils in both low and high oxygen tensions display increased structural rigidity and generate more neutrophil extracellular traps. This may impede their transit through the lung and increase capacity to cause lung tissue/vascular damage. The key goal of this proposal is to understand how oxygen regulates neutrophil biomechanics to promote lung injury and identify novel targets that mediate oxygen-dependent behaviour, aiming to prevent neutrophil sequestration in the lung and mitigate acute lung injury.