Alveolar Epithelial Damage and Dysfunction as Common Features of Ischemia/Reperfusion Injury and Primary Graft Dysfunction in Lung Transplants

Abstract

Ischemia reperfusion injury (I/R) is the major cause of primary graft dysfunction (PGD) after lung transplantation. I/R and PGD feature endothelial/alveolar epithelial damage, lung edema and inflammation. Edema resorption then depends on the restoration of alveolar epithelial integrity and the ability of alveolar cells to reabsorb Na+ (through ENaC channels) and fluid. We hypothesized that alveolar epithelial damage, and repair, are critical in PGD pathophysiology, and resolution. Therefore, our aim is to identify novel biomarkers and therapeutic targets associated with I/R using cellular and animal models as well as human samples from lung transplants. The impact of a protocol mimicking hypothermic ischemia and reperfusion was first tested on primary rat alveolar epithelial cell cultures. Then, an inflammatory stress was induced by LPS in a porcine model of ischemia/ex-vivo reperfusion. Finally, lung biopsies from the donor grafts were collected during lung transplantations and the PGD grade within the recipients were then determined. In primary alveolar cell cultures, we showed altered ENaC and tight junction protein (ZO-1) expression following the I/R mimicking protocol. A decline in transepithelial resistance and reduced alveolar wound repair rates were also observed. Treatment with a KvLQT1 K+ activator (R-L3) accelerated the repair rates and enhanced barrier integrity (ZO-1 staining) and ENaC protein expression. In the porcine model, alveolar damage, lung edema, exacerbated inflammatory response and decreased ENaC expression were observed after LPS-exposure. Preliminary data from lung transplant samples indicated an inflammatory response and decreased ENaC and ZO-1 expression in the donor graft among patients subsequently developing a PGD. Our data support the hypothesis of alveolar epithelial dysfunction after I/R injury. We will now investigate a potential relationship between donor phenotypic factors, markers of epithelial damage/dysfunctin within the grafts, inflammatory levels and the subsequent development of PGD in lung recipients.