Surfactant phospholipid metabolism and respiratory failure in lung transplantation

Abstract

Primary graft dysfunction (PGD) after lung transplantation is a multi-factorial syndrome of postoperative lung injury that is similar to the acute respiratory distress syndrome. PGD is a major risk factor for chronic lung allograft dysfunction and perioperative death. Pulmonary surfactant dysfunction is frequently seen in PGD and contributes to respiratory failure. Surfactant is primarily comprised of lipids, of which phosphatidylcholine (PC) species predominate. Dipalmitoylphosphatidylcholine (DPPC) is the most surface-active species that normally represents over half of all airway PC content. Combining electrospray ionisation tandem mass spectrometry with deuterium labelling of Kennedy’s PC synthetic pathway can assess surfactant phospholipid flux, with a molecular specificity that differentiates between lipids with unique functions. This technique was used to quantify perioperative phospholipid metabolic disruption in lung transplantation. The same technique was used in an ex vivo human lung model to isolate the pulmonary contribution to systemic phospholipid metabolism, and evaluate Kennedy pathway integrity during ex vivo lung perfusion (EVLP). Airway DPPC content was severely reduced after transplantation, and was associated with impaired oxygenation. Variations in Kennedy pathway activity were associated with impaired graft function for months after transplantation. Perioperative flux of phospholipids, like DPPC and polyunsaturated PC species, were strong predictors of poor postoperative lung function. Deuterium labelled ex vivo experiments confirmed continued Kennedy pathway dependent surfactant phospholipid synthesis during EVLP, and could represent a protective mechanism against PGD in clinical EVLP. Ex vivo lungs secreted a different phospholipid profile into the perfusate that is enriched with polyunsaturated PC when compared to the airways, providing compelling evidence of the previously hypothesized basolateral phospholipid secretion by the alveolar epithelium. These polyunsaturated PC species are precursors of numerous inflammatory mediators, and could contribute to PGD. Continued investigation of phospholipid flux through the Kennedy pathway could identify novel biomarkers and therapeutic targets in lung transplantation.Open Acces