Surfactant is a lipoprotein complex that functions at the interface of the airspaces and the lung epithelium 1) to reduce surface tension and 2) to function in host defense against infection. An adequate pool of functional surfactant must be maintained in order to execute both of these functions. Both in vivo and in vitro studies have shown that surfactant levels are altered in during lung injury, infection, and/or inflammation. It is not known if these alterations in surfactant are a cause or consequence of the lung injury. The goal of this proposal is to investigate the factors that contribute to maintenance of a functional pool of surfactant, and to investigate the functional consequences of changes in surfactant levels in the acutely injured lung. Surfactant pool size is maintained by balancing the contributions of synthesis of new surfactant, secretion, and clearance. Our preliminary data and published work from other laboratories show 1) that the levels of surfactant change in the acutely inflamed lung, a rat model of intratracheal lipopolysaccharide (LPS) injury, 2) that the levels of surfactant proteins and lipids are differentially regulated, and 3) that perturbations in surfactant clearance contribute significantly to the alterations in pool size. In addition, a consequence of SP-A deficiency is an increased susceptibility to lung inflammation. The hypothesis to be tested is that surfactant levels are altered in acute lung injury, at least partially via changes in surfactant clearance pathways, and that these alterations result in an increased susceptibility to further inflammation. This hypothesis will be tested by investigating 4 specific aims.
Specific aim number 1: Define the changes in alveolar surfactant pool sizes and the in vivo surfactant clearance pathways in the inflamed lung.
Specific aim number 2: Determine in vitro the contributions of cells isolated from the inflamed lung (neutrophils, macrophages, and type II cells) to surfactant metabolism.
Specific aim number 3: Investigate the mechanism by which binding of surfactant proteins to activated cells is regulated.
Specific aim number 4: Investigate the functional consequences of an SP-A deficiency (in SP-A -/- mice) in the response to LPS-induced lung inflammation. These studies should provide information relevant to design of rationale therapies for treatment of inflammatory lung disease.
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