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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL066410-02
Application #
6490760
Study Section
Lung Biology and Pathology Study Section (LBPA)
Program Officer
Harabin, Andrea L
Project Start
2001-01-01
Project End
2004-12-31
Budget Start
2002-01-01
Budget End
2002-12-31
Support Year
2
Fiscal Year
2002
Total Cost
$290,250
Indirect Cost
Name
University of California San Francisco
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Lopez-Rodriguez, Elena; Cruz, Antonio; Richter, Ralf P et al. (2013) Transient exposure of pulmonary surfactant to hyaluronan promotes structural and compositional transformations into a highly active state. J Biol Chem 288:29872-81
Lopez-Rodriguez, Elena; Ospina, Olga Lucia; Echaide, Mercedes et al. (2012) Exposure to polymers reverses inhibition of pulmonary surfactant by serum, meconium, or cholesterol in the captive bubble surfactometer. Biophys J 103:1451-9
Picardi, M Victoria; Cruz, Antonio; Orellana, Guillermo et al. (2011) Phospholipid packing and hydration in pulmonary surfactant membranes and films as sensed by LAURDAN. Biochim Biophys Acta 1808:696-705
Merrill, J D; Ballard, P L; Courtney, S E et al. (2011) Pilot trial of late booster doses of surfactant for ventilated premature infants. J Perinatol 31:599-606
Lu, Karen W; Pérez-Gil, Jesús; Echaide, Mercedes et al. (2011) Pulmonary surfactant proteins and polymer combinations reduce surfactant inhibition by serum. Biochim Biophys Acta 1808:2366-73
Lopez-Rodriguez, Elena; Echaide, Mercedes; Cruz, Antonio et al. (2011) Meconium impairs pulmonary surfactant by a combined action of cholesterol and bile acids. Biophys J 100:646-655
Iwanicki, Janetta L; Lu, Karen W; Taeusch, H William (2010) Reductions of phospholipase A(2) inhibition of pulmonary surfactant with hyaluronan. Exp Lung Res 36:167-74
Stenger, Patrick C; Alonso, Coralie; Zasadzinski, Joseph A et al. (2009) Environmental tobacco smoke effects on lung surfactant film organization. Biochim Biophys Acta 1788:358-70
Lu, Karen W; Pérez-Gil, Jesús; Taeusch, H William (2009) Kinematic viscosity of therapeutic pulmonary surfactants with added polymers. Biochim Biophys Acta 1788:632-7
Stenger, Patrick C; Palazoglu, Omer A; Zasadzinski, Joseph A (2009) Mechanisms of polyelectrolyte enhanced surfactant adsorption at the air-water interface. Biochim Biophys Acta 1788:1033-43

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