Author:

Abstract:

Long term survival after lung transplantation remains hampered by the development of chronic rejection. A lot of risk factors for the development of chronic rejection are already established and partly confirmed in this manuscript (acute rejection, lymphocytic bronchiolitis, infection, colonization with Pseudomonads, elevated neutrophilia), but based on this research we can add daily variations in particulate matter as a new risk factors for lymphocytic bronchiolitis.There is increasing evidence, indicating that chronic rejection is no longer a homogeneous process and that different phenotypes within chronic rejection exist. One group of patients responds to treatment with azithromycin and are denominated NRAD patients. Performing broncho-alveolar lavage in these patients, reveals a high % of neutrophils and a lot of elevated pro-inflammatory mediators (MMP-9, IL-8, MPO,…), while biopsies show a higher number of IL-17/CD8+ lymphocytes in the airway submucosa. After treatment with azithromycin, mediators decrease, but still remain elevated compared to stable patients. In the non-responsive patients, no single mediator was found to be differentially expressed compared to stable patients. With a combination of CT, μCT and histopathology, we further studied these non-responsive patients and showed that 60% of the airways obstruct from generation 9 till 14. The number of terminal bronchioles was not decreased compared to unused donor lungs. However, proximally, we could find obstruction of the airways. The airways obstructed in 2 different ways: one lesion showing collagenous obstruction and another one only narrowing of the airway without extra collagen. These findings could help us to finally unravel the pathophysiology of chronic rejection after lung transplantation and to achieve a survival comparable to other solid organ transplantations.