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. ? ? ?
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