P033 Predictive biomarkers, and therapeutic targets, from the donor graft associated with the development of primary graft dysfunction after lung transplantation in cystic fibrosis patients

Background: Lung transplantation is the only therapeutic option for patients with terminal lung disease, including cystic fibrosis (CF). Unfortunately, primary graft dysfunction (PGD), the first cause of death in the perioperative period, is associated with lower survival rates. We hypothesized that alveolar dysfunction in the donor graft, after cold ischemia and inflammation, is a critical component of PGD pathophysiology in lung recipients. Objective: The goal of this study was 1) to study the impact of inflammation and ischemia on alveolar integrity and 2) to identify markers of alveolar damage and dysfunction within the donor grafts before PGD development in lung recipients. Methods: We first used cellular and animal models of cold ischemia and inflammation. We also collected samples and data from 172 lung donors and their recipients (including 67 CF patients). The PGD grade was determined according to ISHLT guidelines. The levels of inflammatory, alveolar damage/integrity, and functionality markers were then determined. Results: Analyses of primary alveolar cell cultures and porcine lung tissues, after cold ischemia, revealed a reduction in tight junction (ZO-1) protein, ENaC and CFTR expression. Among lung recipients, we found that cold ischemia duration of the donor graft, although below the recommended threshold, is associated with increased PGD scores. Histological analysis and immunostainings of lung biopsies before graft transplantation showed alveolar inflammation, epithelial damage as well as reduced ZO-1, ENaC and CFTR expression, among PGD recipients. Importantly, we observed a relationship between reduced ENaC/CFTR channel expression, higher cold ischemia duration, and PGD scores. Conclusion: This study provides novel insights into epithelial damage/dysfunction within the donor graft associated with PGD development in the recipient and paves the way for the identification of novel predictive biomarkers and therapeutic targets for CF lung transplants.