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F18. CHRONIC ASPIRATION OF GASTRIC CONTENTS CONTRIBUTES TO ACCELERATED PULMONARY ALLOGRAFT DYSFUNCTION IN A MODEL OF RAT LUNG TRANSPLANTATION
Matthew G Hartwig, Bin Li, James Z Appel, III, Chong-chao Hsieh, Shu S Lin, William Parker, R. Duane Davis; Durham, NC

Objective: Emerging clinical evidence suggests that gastro-esophageal reflux disease (GERD) may contribute to pulmonary allograft dysfunction. Analysis of clinical data demonstrates an association between GERD and reduced pulmonary function, bronchiolitis obliterans syndrome, and more severe acute rejection burden. Furthermore, fundoplication of recipients with GERD is associated with reduced rates of BOS and fewer acute rejections. We hypothesized that in a rat model of lung transplantation, chronic aspiration of gastric contents would contribute to greater pulmonary allograft dysfunction.
Methods: Four groups of rats were used for this study. Groups 1 and 2 included WKY-to-F344 left lung allograft recipients analyzed at 1 and 2 months posttransplant (1MTx and 2MTx, respectively). Groups 3 and 4 involved WKY-to-F344 left lung transplants with 1 and 2 months of chronic aspiration into the left lung allograft (1MTxG and 2MTxG, respectively). Chronic aspiration consisted of 0.5cc/kg of filtered gastric contents injected into the left lung once a week for the duration of the study beginning one week following transplantation. No immunosuppression was used in any recipients. Mixed lymphocyte culture (MLC) assays were used to discern direct versus indirect stimulation of recipient T-cells between groups. Serum cytokine analysis was performed using a Bioplex Cytokine Assay System. All groups were also compared grossly and histologically.
Results: The 1MTx and 2MTx groups (n=9) demonstrated diffuse ISHLT grade 3-4 acute rejection. Grossly, 6 of 9 (67%) 1MTx and 2MTx allografts were inflated and perfused normally. In contrast, all 7 allografts subjected to repetitive aspiration (1MTxG and 2MTxG) demonstrated near complete obliteration of lung parenchyma with diffuse fibrosis and complete loss of graft function (Fisher’s Exact Test, p = 0.01). Serum cytokine analysis demonstrated no statistically significant differences in serum levels of IL-1alpha, IL-1beta, IL-2, IL-4, IL-6, IL-10, TNF-alpha, and IFN-gamma. However, MLC assays revealed hyperresponsive direct and hyporesponsive indirect pathways of T-cell stimulation for the allograft recipients undergoing chronic aspiration. On the contrary, the recipients in the 1MTx and 2MTx groups without aspiration demonstrated equal levels of direct and indirect T-cell stimulation.
Conclusions: In an F344-to-WKY rat orthotopic lung transplant model, chronic aspiration of gastric contents is associated with an augmented direct pathway of antigen presentation T-cell stimulation and accelerated loss of allograft function.

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