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Title: The involvement of the NLRP3 inflammasome in donor lung injury
Author: Major, Triin
ISNI:       0000 0004 7971 1031
Awarding Body: University of Manchester
Current Institution: University of Manchester
Date of Award: 2018
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Lung transplantation remains the only feasible treatment option for people with end-stage pulmonary disease who do not respond to other therapeutic strategies. However, the demand for donor lungs greatly outweighs the availability of organ supply, which results in waiting list mortality. Lungs are extremely susceptible to damage within the donor environment, and only 20% of donor lungs meet the criteria for standard transplantation. This has led to increased use of marginal donor lungs, which in turn increases the risk of complications such as rejection and primary graft dysfunction. Ex vivo lung perfusion (EVLP) is used to evaluate, and also to improve pulmonary function in these marginal donor lungs. Interleukin-1B (IL-1B), a potent pro-inflammatory cytokine has been identified as a prognostic indicator of non-recovery in human EVLPs. The release of IL-1B is dependent on the assembly of inflammasome, a large multiprotein complex. The hypothesis of these studies was that inhibiting the NLRP3 inflammasome formation would reduce the release of active IL-1B thereby decreasing the inflammatory response during EVLP, thus potentially encouraging organ recovery. NLRP3 inflammasome inhibitor was introduced into porcine ex vivo organ perfusion systems of healthy lungs and damaged kidneys. Organ function was assessed along with the inflammatory profile of the organs in the control and treatment groups. Furthermore, the levels of other inflammasome-related inflammatory mediators IL-1B, pro-IL-1B, caspase-1 and IL-18 were measured in human EVLP perfusate and bronchoalveolar lavage samples from lungs that were transplanted and lungs that were discarded. Lastly, the concentrations of these mediators were assessed in plasma samples of lung transplant recipients immediately before and up to 72 hours post-operatively, and correlated the values with pulmonary oxygenation capacity as an indicator of lung function. Whilst a decrease in the extracellular inflammasome particles in the porcine ex vivo perfusions occurred, there were no differences between the control and the inhibitor groups in terms of their cytokine profiles, cellular outflow or organ function. This demonstrated that despite the inhibitor therapy reducing inflammasome activity, it did not convey protection or promote organ recovery. In the perfusate of human lungs that did not recondition during EVLP and were rejected for transplant, a significant increase in pro-IL-1B, the inactive precursor molecule expressed intracellularly, was detected. This suggests that inflammasome inhibition therapy alone may not protect donor lungs from injury or promote recovery, and that pro-IL-1B is released following cell death rather than actively secreted as part of a specific inflammatory process.
Supervisor: Yonan, Nizar ; Fildes, James ; MacDonald, Andrew Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available
Keywords: evlp ; ex vivo lung perfusion ; IL-1B ; lung injury ; nlrp3 inflammasome ; pro-IL-1B ; organ perfusion ; lung transplantation ; inflammasome