Pulmonary surfactant dysfunction in pediatric cystic fibrosis: Mechanisms and reversal with a lipid-sequestering drug.

BACKGROUND: Airway surfactant is impaired in cystic fibrosis (CF) and associated with declines in pulmonary function. We hypothesized that surfactant dysfunction in CF is due to an excess of cholesterol with an interaction with oxidation. METHODS: Surfactant was extracted from bronchial lavage fluid from children with CF and surface tension, and lipid content, inflammatory cells and microbial flora were determined. Dysfunctional surfactant samples were re-tested with a lipid-sequestering agent, methyl-ß-cyclodextrin (MßCD). RESULTS: CF surfactant samples were unable to sustain a normal low surface tension. MßCD restored surfactant function in a majority of samples.Mechanistic studies showed that the dysfunction was due to a combination of elevated cholesterol and an interaction with oxidized phospholipids and their pro-inflammatory hydrolysis products. CONCLUSION: We confirm that CF patients have impaired airway surfactant function which could be restored with MßCD. These findings have implications for improving lung function and mitigating inflammation in patients with CF.

The development of the pulmonary surfactant system in California sea lions.

Pulmonary surfactant has previously been shown to change during development, both in composition and function. Adult pinnipeds, unlike adult terrestrial mammals, have an altered lung physiology to cope with the high pressures associated with deep diving. Here, we investigated how surfactant composition and function develop in California sea lions (Zalophus californianus). Phosphatidylinositol was the major anionic phospholipid in the newborn, whereas phosphatidylglycerol was increased in the adult. This increase in phosphatidylglycerol occurred at the expense of phosphatidylinositol and phosphatidylserine. There was a shift from long chain and polyunsaturated phospholipid molecular species in the newborn to shorter chain and mono- and disaturated molecular species in the adult. Cholesterol and SP-B concentrations were also higher in the adult. Adult surfactant could reach a lower equilibrium surface tension, but newborn surfactant could reach a lower minimum surface tension. The composition and function of surfactant from newborn California sea lions suggest that this age group is similar to terrestrial newborn mammals, whereas the adult has a "diving mammal" surfactant that can aid the lung during deep dives. The onset of diving is probably a trigger for surfactant development in these animals.