Chronic rejection of transplanted lungs is serious problem, with current graft survival at 5 years of only 50%. Given that transplantation is the only therapy for thousands of patients with end-stage lung disease, the repair and prevention of organ failure is a critical area of research. Progenitor cells derived from bone marrow have been shown to respond following lung injury in both mice and humans. Different populations of progenitors have been shown to have conflicting functions. Specifically, Clara cell secretory protein (CCSP)⁺ epithelial progenitors contribute to repair and lung maintenance, while collagen-1⁺ fibroblast progenitors (fibrocytes) are associated with lung fibrosis, impaired lung function, and reduced survival. Our preliminary data show that patients with end-stage bronchiolitis obliterans syndrome (BOS) have a significantly increased ratio of fibrocytes to CCSP⁺ cells in the peripheral circulation. The current study aims to elucidate the validity of progenitor cell numbers and phenotype in predicting and monitoring BOS using the primary outcome of BOS status and further assessing covariate of disease. In addition we will examine the effect of immunosuppressive drugs on lung progenitor cell mobilization from the bone marrow using both clinical patient data and animal models of drug delivery, with the aim of determining specific protocols that optimize the patients’ own regenerative cell capacity and minimize the contribution of fibrotic cells. We further hypothesize that a unique combination of cytokines and chemokines is responsible for progenitor cell recruitment to damaged lungs. Utilizing proteomic techniques, patient plasma samples will be analyzed for specific targets involved in stem cell recruitment. Future directions will include development of specialized regenerative medicine therapies to enhance reparative cell activity and inhibit fibrotic cell function.

Final Report