Obliterative bronchiolitis (OB) is a fibroproliferative disorder seen following lung transplantation in which mesenchymal cells and their connective tissue products accumulate within small airways, causing progressive airflow obstruction, disability and often death. This disease is thought to be due to an immune mediated airway epithelial injury which initiates an uncontrolled fibroproliferative response. Platelet-derived growth factor (PDGF), a moiety which directs the migration and replication of mesenchymal cells, has been strongly implicated in several fibroproliferative pulmonary disorders, including OB. We hypothesize that inhibition of PDGF can limit the fibroproliferation within airways seen following lung transplantation. This proposal seeks to interdict the action of this ligand locally within transplanted airways by transfecting a dominant negative mutant PDGF receptor to airways of an animal model of transplant fibrosis. To accomplish this, we will 1) create a series of PDGF receptor deletion mutants from full length receptor cDNA, and test these mutants for ability to bind ligand and function as a dominant negative in vitro; 2) develop a gene transfer system which allows efficient expression of the mutant receptor in airway epithelium by utilizing an adenovirus vector, and 3) test the dominant negative PDGF receptor for its ability to inhibit fibroproliferation in an animal model of transplant airway fibrosis.
|King, Melissa B; Pedtke, Andrew C; Levrey-Hadden, Helene L et al. (2002) Obliterative airway disease progresses in heterotopic airway allografts without persistent alloimmune stimulus. Transplantation 74:557-62|