Over the last decade there has been an enormous increase in survival of very low birth weight infants. Survival at 500-750 gm is about 50%, yet 66% of these infants will have lung damage as a result of the supportive care necessary for survival. This lung injury, bronchopulmonary dysplasia, has a high morbidity and delayed mortality. Thus, because of insufficient pulmonary surfactant synthesis and our hypothesis that antioxidant defense mechanisms are inadequate, a high incidence of morbidity and mortality associated with inhalation of high concentration of oxygen is problematic for this pediatric population. We will test if the alveolar epithelium is a significant source of oxygen radical generation in the adult and neonatal lung and then define biochemical and functional changes in alveolar epithelial cells occurring secondary to free radical stress. We hypothesize that unique biochemical and anatomical characteristics of the alveolar epithelium can be exploited to enhance cell uptake of antioxidant enzymes and alpha-tocopherol, thus rendering the neonate more oxidant resistant. This will be done by the novel approaches of a) delivery of liposomes to lung by an airway route, b) incorporating antioxidant enzymes into surfactant-derived liposomes, c)incorporating surfactant apoproteins (which enhance type 11 cell lipid uptake) into liposomes and, d) attaching type 1 and type 11 cell-specific lectins onto liposomal surfaces. A combination of biochemical, functional, histopathologic and immunocytochemical endpoints will assess enzyme delivery processes to the alveolar epithelium in vitro and in vivo, and extent of antioxidant protection. These experiments will serve as the basis for effective pharmacologic intervention in limiting the sequelae of oxygen treatment in the newborn (i.e. bronchopulmonary dysplasia) and will establish a sound understanding of the basic mechanisms of O2 induced injury to the neonatal alveolar epithelium.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Pathology A Study Section (PTHA)
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University of Alabama Birmingham
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