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Investigating the mechanisms of bronchiolitis obliterans in a murine tracheal transplant model Cheah, Stefanie

Abstract

Post-lung transplant bronchiolitis obliterans (BO) is the leading cause of morbidity and mortality in lung transplant patients and is the major limitation to long-term transplant survival. BO is believed to be primarily the result of repetitive immune-mediated injury to the airway epithelium resulting in an aberrant repair phase of fibro-proliferation that occludes the bronchiole lumen. The first aim of this thesis was to investigate the use of gene therapy to prevent airway epithelial cell (AEC) apoptosis and the development of obliterative airway disease (OAD) using the murine heterotopic tracheal transplant model of BO. Using lentivirus-mediated transduction of the anti-apoptotic protein, Bcl-2, an improvement in epithelial integrity was observed in 14 day tracheal allografts. However, in 28 day allografts, the airway epithelium was lost and the lumens of the tracheae were occluded with fibrotic material in all treatment conditions. These results were caused by difficulties in achieving efficient transduction of the airway epithelium and highlighted the need for futures studies using new mechanisms of gene transfer. Secondly, the role of latent-TGF-β1 activation in the fibrotic processes of OAD was also examined. A synthetic peptide of the thrombospondin-1 (TSP-1) receptor, CD36, was used to block activation of latent-TGF-β1 and inhibit OAD. In a comparison of transplanted tracheae treated with the peptide or PBS alone, allografts that received the peptide demonstrated a lower mean luminal occlusion score than the PBS control allografts. In summary, results from this thesis demonstrated the complexity of gene transfer to the airway epithelium and the need for further exploration in order to achieve ideal transgene expression of anti-apoptotic proteins to prevent the loss of the AECs and the development of OAD. In addition, the preliminary findings on the role of latent-TGF-β1 activation in the fibrotic processes of OAD provide an interesting area of study for future research and a potential therapeutic target for the inhibition of BO after lung transplantation.

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Attribution-NonCommercial-NoDerivatives 4.0 International

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