Surfactant dysfunction in cystic fibrosis: Mechanisms and reversal with a cyclodextrin drug

Introduction : Surfactant dysfunction in cystic fibrosis contributes to longitudinal declines in pulmonary function and susceptibility to infection. The cause of the dysfunction is not fully understood. Aims and objectives: To determine the role of cholesterol and oxidation of unsaturated phospholipids in surfactant dysfunction and to attempt reversal of the dysfunction with methyl-β-cyclodextrin (MβCD). Methods : Surfactant was extracted from surplus broncho-alveolar lavage (BAL) fluid obtained for routine diagnostic purposes in a paediatric population of CF patients. BAL from lung healthy children was used as control. Surfactant function was measured in a captive bubble surfactometer (CBS). Cultures for microbial pathogens, differential cell counts and lipid biochemistry were assayed. Results : Cholesterol concentration and neutrophils were significantly elevated in the CF BAL compared to controls. Surfactant function was markedly impaired in all but 3 of the 25 CF children. Surfactant from 16 CF children with dysfunctional surfactant were retested after incubation with MβCD; 14 of 16 were restored to normal function. In vitro mechanistic studies revealed that the dysfunction could be attributed to both excess cholesterol and an interaction between cholesterol, oxidized phospholipids and pro-inflammatory hydrolysis products of phosphatidylcholine; free fatty acids and lysophosphatidylcholine. Conclusion : This study reveals a previously unappreciated consequence of disturbance in pulmonary lipid homeostasis in causing surfactant dysfunction in cystic fibrosis. The dysfunction can be reversed in vitro in a majority of patients with a drug that sequesters lipids. Funded by AIHS/CRIO.