Obliterative bronchiolitis (OB) is a frequently fatal complication of lung transplantation characterized by dyspnea and evidence of airflow obstruction. This proposal details a plan of research to identify methods of preclinical detection of OB by analysis of bronchoalveolar lavage (BAL) fluid constituents. The histopathologic appearance of OB and available experimental data suggest that two interdependent but distinct processes occur. First, bronchiolar lymphocytic inflammation is seen and second, a fibroproliferative response, characterized by migration and replication of mesenchymal cells, ensues and leads to airway fibrosis. The preclinical detection of OB will depend on identification of sensitive markers of these processes. Available information regarding non-pulmonary allografts and preliminary studies of OB indicate that injury of graft structures is mediated by CD8+ lymphocytes. Therefore, the first specific aim of this proposal is to test the hypothesis that increased numbers and activity of CD8+ lymphocytes can be measured in BAL fluid prior to clinically- detectable OB. Migration and replication of mesenchymal cells are signalled by a circumscribed set of peptide growth factors. The second specific aim of the proposed research is to test the hypothesis that increased production of the potent mesenchymal cell growth factor, platelet-derived growth factor (PDGF), can be detected in BAL fluid prior to clinically-detectable OB. The design of the proposed investigation will be 1) To compare BAL fluid constituents (e.g., CD8+ lymphocytes, PDGF concentration) in patients with OB with other patients during infection, acute rejection and clinically quiescent intervals; and 2) To assess the predictive value of these measurements by analysis of serial samples obtained from patients before and after the development of OB. Methods used to identify CD8+ lymphocytes will include definition of cell surface phenotypes, donor-antigen specific primed lymphocyte test reactivity, and functional capabilities of BAL-derived lymphocytes. Increased PDGF production will be evaluated by quantitation of PDGF in BAL fluid and by in situ hybridization of BAL macrophages to detect PDGF mRNA. By identifying such markers it is the overall goal of this investigation to provide the scientific basis for interventions designed to interdict the development of OB by inhibiting immune-mediated bronchiolar injury and subsequent bronchiolar fibrosis prior to the development of irreversible airflow obstruction.
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