Alpha 1 Antitrypsin Treatment of Donor Lungs: A Translational Pathway to Clinical Application

Lung transplantation is a life-saving therapy for patients suffering from end stage lung diseases. Despite the many advances in the field, there is a clear shortage of donors primarily explained by the low utilization rate of the donor lungs offered for transplant. This underutilization is mainly a consequence of the surgeons being cautious about using more marginal lungs, because of the concern that patients will develop primary graft dysfunction (PGD) after transplant. PGD accounts for 30% of the mortality seen during the first month after transplant and it is also related to worse long term survival. Ischemia reperfusion injury (IRI) is a well-known contributing factor to the development of PGD. There is currently no therapy to prevent or treat PGD. In order to examine potential therapies to decrease IRI and reduce the incidence of PGD, there is a need for a relevant large animal lung transplant survival model. A1AT is a serine protease inhibitor, its main function is to act as an antiprotease for neutrophil elastase. It acts like an acute phase protein increasing its concentration during inflammation. A1AT as a drug was purified from human plasma for A1AT deficiency patients. Subsequent studies have shown that A1AT has anti-inflammatory effects in different settings. We have been studying the effect of A1AT in ischemia reperfusion injury in a systematic translational research approach testing its effects in progressively more complex models. Our hypothesis was that A1AT administered before transplantation in an attempt to reduce ischemia reperfusion injury would not have any detrimental side effects, and that A1AT dispensed to EVLP perfusate would improve human donor lungs that were previously rejected for transplantation. The first part of the thesis is centered in developing a relevant pig lung transplant survival model to later on be able to test potential therapeutics to prevent PGD. The second part of this work details the studies done to test alpha-1 antitrypsin (A1AT) in the pig single lung transplant survival model. Using the previously developed pig lung transplant survival model we were able to prove that A1AT is safe, well tolerated and if given to lung transplant recipient animals prior reperfusion, has beneficial effects including faster recovery and improved lung function after transplant. For the third part of this thesis we used ex vivo lung perfusion (EVLP) as a platform to treat human lungs with A1AT. We explored the effect of A1AT treatment given during EVLP to injured human lungs that were not suitable for transplantation. For each case we divided the double lung block and treated one of the lungs in a randomized and blinded fashion. Using this approach we were able to assess the treatment effect of A1AT in the treated lung compared with the untreated one (both from the same donor), as well as compare all cases together (treatment vs control). A1AT was shown to have a beneficial effect on lung function measured by oxygenation function (pO2) and compliance. Biologically, A1AT treatment reduced lung endothelial injury (protected tight junctions) and decreased important pro-inflammatory cytokines that are relevant to endothelial dysfunction. A1AT has been proven to have beneficial anti-inflammatory and immunomodulatory effects. A1AT is an already approved drug that has shown to be well tolerated and has the potential to improve human donor lungs that were previously rejected for transplantation. Based on our findings, we are confident to move forward with a randomized prospective clinical trial to use A1AT to prevent PGD in human lung transplantation.

Keywords: Donor
Ex vivo lung perfusion
Ischemia Reperfusion Injury
Lung Transplantation
Neutrophil elastase
Primary Graft Dysfunction
Advisor: Keshavjee, Shaf