The parent application deals with the regulation of the expression of pulmonary surfactant protein-A. Another major research interest of the PIs of the original and the FIRCA application is the adenovirus-mediated gene transfer. Recombinant adenoviruses have been used to transfer a variety of genes and cDNAs to the respiratory epithelium. The host immune response limits the extent and duration of adenovirus-mediated gene transfer in the lung. The host response to recombinant adenovirus includes acute inflammation, as well as both TH1 and TH2 cell responses leading to clearance of the transfected cells and production of neutralizing antibody to the virus. The PIs of the parent and FIRCA application have recently demonstrate that administration of recombinant adenovirus to the airway injured bronchiolar and alveolar epithelial cells is associated with an accumulation of neutrophils and macrophages. This inflammatory response is associated with accumulation of surfactant proteins A and B in the airways. Considering the importance of nitric oxide and related oxidants in various forms of inflammation, and considering the importance of peroxynitrite-mediated modifications of SP-A in the context of pulmonary injury, the investigators have collected preliminary data which are consistent with the proposal that SP-A becomes nitrated because of the expression of iNOS and the production of peroxynitrite in pulmonary inflammation associated with adenoviral gene transfer.
The specific aims of the FIRCA proposal are the following: 1. To investigate the nitration of pulmonary SP-A in inflammation associated with adenoviral gene transfer, and the changes in the function of SP-A under these conditions. 2. To investigate the expression of iNOS in pulmonary inflammation associated with adenoviral gene transfer. 3. To investigate whether inhibition of iNOS and scavenging of peroxynitrite attenuates the pulmonary inflammation and the changes in the pulmonary SP-A function during adenovirus-mediated gene transfer. The proposed experiments will be performed in a murine model and will enhance an understanding of the oxidative/nitrative modification of surfactant proteins in inflammation, and may provide new therapeutic possibilities for improved efficacy of adenovirus-mediated gene transfer.
