- Dr. Kenneth Fang, Principal Investigator
- Mr. Anthony Cruz, Associate
- University of California, San Francisco, USA
- Role of Mast Cells in Bronchiolitis Obliterans in a Tracheal Allograft Model of Lung Transplantation
Long-term survival of lung transplant recipients is limited by the development of airway scarring known as bronchiolitis obliterans, which causes irreversible airway narrowing and ventilatory failure. Acute and chronic graft rejection, ischemia-reperfusion injury, and cytomegaloviral infections may contribute to the development of the disease. However, current immunosuppressive regimens do not prevent the disease, and understanding of molecular pathways contributing to bronchiolitis obliterans remains poor. Lung transplant tissues demonstrate an overabundance of mast cells in the vicinity of the airways and lymphocytic infiltrates, which correlates with the grade of rejection or extent of bronchiolitis obliterans. How mast cells participate in pathways of airway remodeling leading to the development of bronchiolitis obliterans remains unknown. Clarification of cell signaling pathways and mechanisms regulating mast cell degranulation of stored mediators may identify new pharmacologic targets that may attenuate the progression or prevent the onset of bronchiolitis obliterans. To study the role of mast cells, a tracheal transplantation model using donor and recipient mice tracheas will be used to examine the participation of mast cells in immunologic responses. Use of mice with spontaneous or engineered genetic mutations will permit transplantation experiments to determine the necessity of active Kit receptor tyrosine kinase, a mast cell signaling molecule, and whether mast cells are essential for the development of bronchiolitis obliterans. Mice with genetically engineered deficiencies or defects in proteases will permit investigation of the roles of serine proteases and metalloproteinases in the mast cell response to transplantation and the development of airway scarring. Comparing data of transplanted tracheas from mutant mice with those from wildtype mice should demonstrate whether mast cells and degranulation of serine proteases contribute to scarring and disease development, and whether activity of metalloproteinases influences mast cell behavior by regulating signaling mediated by the Kit receptor.