Adult respiratory distress syndrome (ARDS) is a common clinical syndrome, characterized by acute lung injury and respiratory failure that commonly occurs as a result of sepsis. Mortality remains high and new therapies are needed. The Principal Investigator provides pre-clinical evidence that the expression of the alpha-1 antitrypsin gene in the lungs of rabbits and piglets protects from endotoxin induced lung injury. The AAT gene is delivered intravenously, using a specific plasmid-cationic liposome formulation that results in compartmentalized AAT transgene expression within the lung. It is the hypotheses of this application that AAT gene delivery to the lung will protect instrumented unanesthetized sheep from endotoxin induced pulmonary vasoconstriction, pulmonary edema and impaired gas exchange. Utilizing an instrumented unanesthetized sheep model, the PI and co-investigators will: 1) determine the effects of intravenous infusion of plasmid-cationic liposome formulations on systemic hemodynamics, lung mechanics and gas exchange with and without pretreatment with ibuprofen; 2) determine the effects of transfection of the lungs with the AAT gene on endotoxin induced alterations in pulmonary hemodynamics, lung vascular permeability, lung mechanics and gas exchange; and 3) determine whether endotoxin induced lung injury alters the ability to efficiently transfer the AAT gene by intravenous administration of cationic liposome-plasmid complexes, and to determine whether AAT gene delivery to endotoxin injured lungs potentiates preexisting lung injury.
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