Tackling major pitfalls in lung transplantation

Lung transplantation (LTx) is still hampered by two major problems namely organ shortage, which prolongs waiting times and waiting list mortality, and chronic rejection (CR), the most important cause of late morbidity and mortality after LTx. CR is clinically marked by a decline in forced expiratory volume in one second (FEV1) and histologically by obliterative bronchiolitis (OB) lesions. In our research we focused on both these problems. Enlargement of the donor pool can be obtained by using non-heart beating donors (NHBD). These donors die due to cardiac arrest instead of brain-death in heart-beating donors (HBD). We showed that outcome, both short and medium-term, of patients receiving controlled NHBD lungs is equally good compared to HBD recipients and that mortality and the occurrence of CR are not different between both types of recipients. From these studies we can conclude that NHBD can safely be used to enlarge the donor pool. Since the pathogenesis of CR is still not fully understood and the prognosis remains poor, a good animal model is indispensable to unravel the pathogenesis and to improve treatment options. Many animal models have been developed but none truly mimics the human situation. A good animal model should include orthotopic allograft LTx leading to histological OB lesions and all this in a species wherein lung function can be measured repeatedly and which has enough genetic variance to investigate a whole range of pathological mechanisms. We successfully succeeded in developing a new murine model of CR departing from an orthotopic left LTx. Clear OB lesions were seen in 25-50% of the mice, depending on the time-point after LTx. This model opens new perspectives in unraveling the pathogenesis of CR and exploring new treatment options.status: publishe