Relationship between Phenotypic Characteristics from the Donors, Predictive Biomarkers from the Donor Grafts and the Development of Primary Graft Dysfunction in Lung Transplant Recipients

Abstract

Purpose Lung transplantation is the only therapeutic option for patients with a terminal lung condition. Unfortunately, survival rates after transplantation remains too low. Primary graft dysfunction (PGD) is the first cause of death in the perioperative period and is associated with acute respiratory distress syndrome (ARDS), higher risk of lung infections, chronic rejection, and lower survival rates. We hypothesized that the alveolar epithelial dysfunction in donor grafts and then in the recipient, is a critical component of PGD pathophysiology. Our goal was to identify markers of alveolar damage and dysfunction in the donor grafts associated with PGD development within recipients. Methods We collected human samples and the clinical data from 174 donors and their recipients at different time points (before, during and after lung transplantation, in the ICU and follow-ups at the transplantation clinic). We also isolated alveolar epithelial cells from donor lung biopsies to assess the expression of integrity (ZO-1) and functionality biomarkers (such as ENaC and CFTR channels, which play a key role in the resorption of lung edema, a key feature of ARDS/PGD). Results Among our cohort of 174 lung transplants, suffering from various lung diseases (i.e. CF, PF/IPF, COPD, PAH), 26% developed a PGD. Several phenotypic factors from donors and intervention/procedures during transplantations were analysed. Among them, we found that although below the defined acceptable limit (6h), the mean duration of cold ischemia of the donor grafts among recipients subsequently developing a PGD was significantly longer (266 min) than the one from non-PGD recipients (233 min). We also demonstrated that alveolar cells, isolated from donor grafts within recipients developing a PGD, featured a severe decrease in ZO-1, ENaC and CFTR expression. Moreover, longer cold ischemia duration was associated with the observed ENaC and CFTR downregulation. Conclusion This study provides novel insights on epithelial alteration within donor graft, associated with subsequent PGD development. Moreover, our data pave the way for the identification of novel biomarkers and therapeutic targets for the restoration of alveolar integrity and functionality, with the ultimate goal to prevent PGD in lung transplants.