Post BMT Lung Injury Pathophysiology

DESCRIPTION (provided by applicant): High dose chemoradiotherapy is used to treat patients with malignancies undergoing BMT. The most common regimen remains high dose Cytoxan (Cy) and total body irradiation (TBI) which has lung i injury (termed idiopathic pneumonia syndrome: IPS) as a major complication. Mortality is at least 75%.We have established murine models using Cy/TBI and alIoBMT. Alveolar type 2 (AT2) cells are responsible for surfactant secretion and fluid and solute clearance. Our central hypothesis is that strategies that preserve, speed regeneration of, or replace AT2 cells will have a major impact on lung repair post-BMT. Cytokines have been shown to regulate the development and proliferation of epithelial cells. Fibroblast growth factor-7 (fgf-7), also known as keratinocyte growth factor (KGF), binds to its receptor, FgfR2-111b, expressed on AT2 cells. Fgf-7 protects AT2 cells from injury induced. Based on the model that AT2 are targets for IPS injury, we hypothesized that fgf-7 pretreatment would prevent AT2 damage or hasten AT2 cell repair after BMT, reducing IPS injury. Our data indicate fgf-7 effects are associated with a reduced frequency of injured AT2 cells. In aim 1, we will determine the efficacy of and mechanism(s) responsible for the effects of fgf-7 on preventing or treating IPS, focusing upon AT2 cells. In aim 2, we will determine whether cellular therapies can be used to prevent or treat IPS injury. We hypothesize that marrow stromal cells (MSCs), also known as mesenchymal stem cells, or multipotent adult progenitor cells (MAPCs) or AT2 cells differentiated from these progenitor cells will result in alveolar re-epithelialization when used alone or along with fgf-7. Since both MSCs and MAPCs have been shown to have the capacity to differentiate into pulmonary epithelial cells, the peri-BMT administration of undifferentiated or AT2 differentiated MSCs and MAPCs offer promise for aiding in lung repair post-BMT. These translatable approaches offer new avenues for the prevention and treatment of IPS.