Our longterm goal is to improve therapy of acute lung injury and acute (adult) respiratory distress syndrome (ALI/ARDS). A prominent feature of these diseases is a leak of serum from lung capillaries into alveolar spaces. Serum causes dysfunction of pulmonary surfactant that in turn leads to increased ventilatory support. Ventilator management leads to progressive lung injury. Our objective is to develop surfactants that can be used therapeutically and that resist the dysfunction caused by serum. A major discovery in the first funding cycle is that hyaluronan (HA - an ionic endogenous glycosaminoglycan), when added to commercially available surfactants prevents or reduces inactivation by serum. Since HA is one of several polymers normally present in alveolar subphase, this finding leads to the novel hypothesis that HA may protect alveolar surfactant, up to a point. It follows that more effective treatment of ALI/ARDS may result from replacement both of surfactant and subphase polymers. In this competitive renewal application, we plan a series of in vitro and in vivo experiments that will fully explore the nature and effects of adding HA to surfactants. In the first specific aim, we will examine the in vitro behavior of HA-surfactant mixtures (and control mixtures) in order to optimize their stoichiometry. Viscosity and surface activity, with and without addition of common surfactant inhibitors, will be examined. Through novel mechanisms described in the proposal, we believe that there are additive positive effects between hydrophobic surfactant proteins and HA. Specifically, we will find whether delivery of surfactant to the alveolar surface is enhanced by addition of HA despite the presence of serum inhibition. Morphological techniques will assess real-time surfactant adsorption, as well as offering static views of surface and subphase surfactant morphology. The second specific aim will test whether beneficial effects of HA-surfactant mixtures last for 12-24 hours and reduce mortality of rats with ALI. In addition, we will find whether HA-surfactant mixtures influence lung edema and inflammation by using standard techniques. Overall this project will not only develop a promising new therapy of ALI/ARDS, but will also foster basic understanding of mechanisms of surfactant inhibition and ways to overcome it.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Harabin, Andrea L
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University of California San Francisco
Schools of Medicine
San Francisco
United States
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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
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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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