Successful application of lung transplantation is hampered by inadequate lung preservation techniques and the frequent development of lung allograft reperfusion injury. This injury is mediated by neutrophils. Inhibition of neutrophil adherence by modulating levels of nitric oxide and prostaglandin metabolites reduces ischemia reperfusion injury in the lung, improves lung graft function, decreases morbidity and mortality and reduces costs. Transfer of genetic material to lung grafts is feasible under circumstances consistent with clinical lung transplantation. The first specific aim of this proposal is to determine ideal circumstances for efficient gene transfer to lung grafts.
In Specific Aim II, neutrophil adherence and lung reperfusion injury will be reduced by modulation of nitric oxide and prostaglandin E2 and prostacyclin. This will be accomplished by augmentation of lung graft levels of genes encoding for inducible nitric oxide synthase and prostaglandin synthase. These studies will be conducted in a sequential series of in vitro rat and canine lung transplant models.
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