A new experimental model for chronic lung allograft damage

Background: The long term survival of human lung allograft recipients is limited by the development of a fatal Bronchiolitis obliterans syndrome (BOS). Both, chronic allograft rejection and alloantigen independent factors like infections seem to contribute to the pathogenesis of BOS, which is still poorly understood. Relevant experimental models involving orthotopic pulmonary transplantation consistently resulting in chronic damage resembling BOS are still missing. The aim of our study is to establish and characterize an experimental model for BOS in the rat, which involves aspects of the most important clinical risk factors, allograft rejection and infections.

Methods: We use the Fischer 344 to Lewis rat strain combination for orthotopic transplantation of the left lung. The right native lung is used as an internal control. Lewis rats were used to perform syngrafts. Transplant recipients are treated with ciclosporine for 10 days after surgery to prevent fatal acute rejection. Four weeks after transplantation (d 28), lipopolysaccharide (LPS) is instilled via the trachea. Graft recipients are sacrificed at different time points before (d 28), and after LPS treatment (d 29–90). Lung tissues are studied by histology, immunohistochemistry and qRT-PCR.

Results: Four weeks after transplantation, before LPS treatment, allografts show an increased expression of the toll-like receptor system, IFN-γ and IFN-γ-dependent chemokines compared to syngrafts. Treatment of allograft recipients with LPS results in severe graft inflammation within one day (d 29). Numerous neutrophil granulocytes and macrophages infiltrate the interstitium, the peribronchial and the perivascular space. On day 33, mild intimal arteritis develops, which worsens during the following days and finally results in severe intimal hyperplasia (d 40–90). Allograft fibrosis is obvious as early as by day 40. Around day 90 post-transplantation, a part of the bronchioles exhibits fibro-proliferative remodeling resembling bronchiolitis obliterans. Chronic damage is almost absent from pulmonary syngrafts and native right lungs.

Conclusion: Our new experimental model for chronic lung allograft damage mirrors important aspects of human BOS. The model will be useful to investigate the pathogenesis of this devastating disease experimentally and to develop new approaches to treat human BOS. More studies are needed to clarify if the changes in the toll-like receptor system of the pulmonary graft increased its susceptibility to BOS.