Artikel
Chronic rejection of lung allografts: insights from a new experimental model
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Autoren
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Srebrena Atanasova
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Alena Evers
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Gabriele Fuchs
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Kathrin Petri
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Martin Obert
- Justus-Liebig Universität Gießen, Neuroradiologie, Gießen
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Andrea Fischer-Heuschkel
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Leatitia Rabin
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Markus Hirschburger
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Daniel Jonigk
- Medizinische Hochschule Hannover, Institut für Pathologie, Hannover
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Winfried Padberg
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
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Veronika Grau
- Justus-Liebig Universität Gießen, Sektion Experimentelle Chirurgie, Gießen
| Veröffentlicht: | 26. April 2013 |
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Gliederung
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Introduction: 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. Relevant experimental models involving orthotopic pulmonary transplantation are still missing. The aim of our study is to establish and characterize an experimental model for BOS in the rat.
Material and methods: We use the Fischer-344 to Lewis rat strain combination to perform orthotopic transplantation of the left lung. The right native lung is left in place und 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 aresacrificed at different time points before (d 28), and after LPS treatment (d 29-90). Lung tissues are studied by histochemistry, immunohistochemistry and qRT-PCR.
Results: Treatment of allograft recipients with LPS four weeks after surgery, 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). Starting on day 40, lung fibrosis is obvious. Around day 90 post-transplantation, a part of the bronchioles exhibits fibro-proliferative remodeling resembling human bronchiolitis obliterans. The mRNA expression of INFγ, TNFα, IL-2, IL-4 and IL-10 is significantly up-regulated in allografts in comparison to syngrafts.
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.
