We have recently found that the addition of certain water-soluble polymers improves the function of surfactants used to treat human lung diseases. For example, animals with lung injury from human meconium improve oxygenation when treated with polymer/surfactant mixtures to a much greater degree than animals treated with surfactant alone. We plan to extend these observations by studying whether this effect is found using different models of lung injury - acid instilled into rat lungs or lung lavage followed by hyperventilation. Lung function after injury and treatment with various surfactant types, dosages, and surfactant additives is assessed by measures of gas exchange, lung mechanics, surfactant activity in bronchopulmonary lavage, white cell influx into alveoli, histology, and fluid and protein flux between capillaries and alveoli. These studies will test whether surfactant/polymer mixtures are more effective than surfactant alone when treating this model of adult respiratory distress syndrome, a serious condition that afflicts > 100,000 patients in the U.S./year. Other investigations will test whether polymers will preserve both good surface activity and the appearance of surface-active forms of surfactant (tubular myelin-like and stacked bilayer structures) in the presence of inactivating substances. We will study surfactant mixtures that contain different amounts of surfactant-associated proteins and polymers, then retest the mixtures after addition of known inactivating substances (like fibrin). These mixtures will be tested in vitro for various attributes-minimum surface tension, resistance to surfactant film penetration with inactivating substances, adsorption, calorimetry characteristics, surface phase transitions, and appearance by light and electron microscopy. Surfactant inactivation is a common and important feature associated with progression of many forms of acute lung injury. Better surfactants that resist inactivation will improve treatment of these diseases.
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