This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The primary limiting factor to long-term survival after lung transplant is bronchiolitis obliterans (BO), characterized by luminal compromise of small airways and by eosinophilic plaques. Clinically, BO is manifest as bronchiolitis obliterans syndrome (BOS), a progressive decline in pulmonary function. During the past several years, our group has reported an association between gastroesophageal reflux disease (GERD) and increased BOS and mortality rates. The prevalence of GERD is particularly common following lung transplantation, approximating 75%. Additionally, our data suggests that surgical correction of GERD may abrogate BOS and mortality. Despite this clinical association, a definitive relationship between GERD and OB has not been established. Furthermore, the mechanisms by which GERD contributes to pulmonary allograft dysfunction have not been elucidated. We recently developed a rat model for pulmonary allotransplantation and methods to simulate GERD in rat lung transplant recipients. Initial data supports interesting cellular and immunologic responses among rat recipients of pulmonary allografts with simulated GERD. We hope to collect sufficient data for an R01 grant for further support. We hope to elucidate cellular and molecular mechanisms by which GERD-induced graft dysfunction occurs in lung transplant recipients. We will obtain advanced radiologic imaging of rat lung transplant recipients to image early posttransplant (within first 5-7 days) to screen for technical failures, which is crucial because the majority of the grafts appear avascular and fibrotic. However, a similar phenomenon occurs in some isograft recipients and we believe that up to 10-30% of allografts may fail due to non-immunologic compromise resulting from surgical procedure failures. Thus, we are interested in advanced imaging modalities that provide more detailed pulmonary anatomy, and perhaps, some measure of pulmonary function or viability. Rats with unacceptable grafts based on imaging would be excluded from further laboratory analysis. Among rats with functioning graphs based on the initial screening studies, GERD will then be induced in one half. The second application for advanced imaging in this model is to distinguish the radiographic and functional differences that develop among rat transplant recipients with induced GERD compared to those without GERD. Ultimately, such technology could have clinical applications, as well in human lung transplant recipients.
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