Diazeniumodiolate Reactivity in Lung Surfactant Media

George Mason University, Fairfax VA

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): Diazeniumdiolates are widely used nitric oxide generating agents in biomedical research studies because of their ability to release nitric oxide (NO) spontaneously at physiological pH. Since evidence from both animal and human studies has demonstrated that inhaled nitric oxide gas can act as a selective pulmonary vasodilator, its use for the treatment of lung disorders has been an active area of investigation. The administration of low concentrations of the gas has been used to treat adult respiratory distress syndrome and to reduce pulmonary vascular resistance in newborn infants. Since direct NO therapy has some severe limitations, the administration of NO to the lung by way of diazeniumdiolates is presently being examined as an alternative means of achieving controlled delivery of nitric oxide. Diazeniumdiolates have been successfully employed as selective pulmonary vasodilators in paucine animal models and they have been administered to a human patient with acute respiratory distress syndrome. In the proposed study, information on the reactivity of diazeniumdiolate substrates in various phospholipid media found in lung surfactant, the surface-active mixture of lipids and specific proteins lining the lung, will be sought. Binding constants for the association of a variety of diazeniumdiolates with phospholipid vesicles will be measured and their effect on NO dissociation rates determined. In particular, interactions with different hydrophilic/hydrophobic interfaces generated by the saturated phosphatidylcholine and unsaturated phosphoglycerols that dominate lung surfactant composition, will be examined. Associations with mixed phospholipid aggregates which are likely to be involved in multiphase transitions central to lung surfactant function will also be explored. Information obtained in the study should be relevant to the application of diazeniumdiolates as NO providers for the study and treatment of lung disease and provide insight into the therapeutic synergy that has been demonstrated during the co-administration of replacement animal surfactant with diazeniumdiolates.