Acute lung injury is characterized by diffuse alveolar damage with injury and death of type I and type II alveolar epithelial cells. Injury to the type II cell is particularly critical as it is the progenitor of the type I cell and is the major source of pulmonary surfactant in the lung. Our laboratory has recently demonstrated the feasibility of airway delivery of genetically engineered alveolar macrophages to the alveolar structures. We present preliminary data that indicate that freshly isolated type II cells can be intratracheally delivered to mice with bleomycin-induced acute lung injury. The donor type II cells can be easily identified and appear to attach to the alveolar wall surface. We propose that these type II cells will subsequently engraft to the alveolar surface; if successful, this may result in functional recovery of the alveolar structures. Furthermore, we have successfully transfected alveolar epithelial cells in vitro and demonstrated resistance to bleomycin-induced DNA damage and cell injury. These cells, referred to as """"""""super type II cells"""""""", may represent a population of donor cells that will engraft more successfully than normal type II cells. Therefore, we hypothesize that: airway delivery of alveolar epithelial progenitor cells to the alveolar structures during bleomycin lung injury will result in engraftment and replacement of the injured alveolar epithelium and will hasten recovery of lung function.
The specific aims of this proposal are: 1) to demonstrate that airway delivery of alveolar epithelial progenitor cells (type II cells, marrow-derived progenitor cells) will localize to the alveolar structures and engraft to the injured alveolar surface during bleomycin-induced acute lung injury, 2) to determine if successful engraftment of alveolar epithelial progenitor cells to the alveolar epithelium will hasten recovery from bleomycin-induced acute lung injury, and 3) to determine if donor type II cells transfected to be more resistant to bleomycin toxicity, i.e. """"""""super type II cells"""""""", engraft more successfully and promote more rapid recovery than normal type II cells. If successful, this model of alveolar tissuegenesis will represent a highly novel therapeutic approach in repair of diffuse alveolar damage during acute lung injury.
| Wu, M; Pasula, R; Smith, P A et al. (2003) Mapping alveolar binding sites in vivo using phage peptide libraries. Gene Ther 10:1429-36 |
