Alpha-1-antitrypsin safely promotes rapid recovery of pigs after lung transplantation

Primary graft dysfunction is an important complication requiring surveillance in the first 3 days after lung transplantation. Currently, there is no effective clinical therapy to prevent or treat primary graft dysfunction. Alpha-1-antitrypsin (A1AT) is a serine-protease inhibitor that inhibits neutrophil elastase and has been used for decades as a safe augmentation therapy for patients with A1AT deficiency. We have previously shown that administration of A1AT results in antiinflammatory and antiapoptotic effects that combat ischemia-reperfusion injury across cell culture, preclinical (rat and pig) nonsurvival lung transplant, and pig ex vivo lung perfusion models. 1 Gao W. Zhao J. Kim H. et al. Alpha1-antitrypsin inhibits ischemia reperfusion-induced lung injury by reducing inflammatory response and cell death. J ​Heart Lung Transplant. 2014; 33: 309-315https://doi.org/10.1016/j.healun.2013.10.031 Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar , 2 Iskender I. Sakamoto J. Nakajima D. et al. Human alpha1-antitrypsin improves early post-transplant lung function: pre-clinical studies in a pig lung transplant model. J ​Heart Lung Transplant. 2016; 35: 913-921https://doi.org/10.1016/j.healun.2016.03.006 Abstract Full Text Full Text PDF PubMed Scopus (44) Google Scholar , 3 Lin H. Chen M. Tian F. et al. α1-Anti-trypsin improves function of porcine donor lungs during ex-vivo lung perfusion. J ​Heart Lung Transplant. 2018; 37: 656-666https://doi.org/10.1016/j.healun.2017.09.019 Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar Before initiating a clinical trial, we further examined the potential clinical benefit and safety of A1AT in a pig single lung transplant 3-day survival model. This model was designed to replicate the clinical setting as closely as possible prior to proceeding to a clinical trial. 4 Mariscal A. Caldarone L. Tikkanen J. et al. Pig lung transplant survival model. Nat Protoc. 2018; 13: 1814-1828https://doi.org/10.1038/s41596-018-0019-4 Crossref PubMed Scopus (26) Google Scholar