Mitochondrial-DAMPs released after lung transplantation promote primary graft dysfunction

Lung transplantation (LTx) often results in primary graft dysfunction (PGD), a form of acute lung injury (ALI) that is responsible for poor short and long-term outcomes. Although the underlying mechanisms that promote PGD are undefined recent evidence has pointed to the involvement of danger associated molecular patterns (DAMPs). Mitochondrial DAMPs (Mt-DAMPS) share the potent immunostimulatory qualities of bacterial pathogen-associated molecular patterns (PAMPs) since they can activate the necrotactic formyl peptide receptor 1 (FPR1) regulating neutrophil migration to injured areas. However, the contribution of the Mt-DAMPs-FPR1 axis to organ transplant injury remains unclear. In a murine orthotopic LTx model of PGD, we detected the release of donor-derived Mt-DAMPs into the injured airways. We also demonstrate that FPR1 expression in the recipient regulates neutrophil intragraft distribution by promoting airways neutrophilia. This effect seems to be specifically associated with the activation of the Mt-DAMPs-FPR1 axis which leads to neutrophil upregulation of adhesion molecules and increased extravascular neutrophil cluster stability. As a consequence of FPR1 expression, we demonstrated prolonged neutrophil retention into the injured airways and exacerbation of the ALI. In a prospective study of 62 human lung recipients, circulating Mt-DAMPs, in the form of mitochondria DNA (Mt-DNA), were increased after LTx and the higher perioperative levels were predictive of severe late PGD. In conclusion, this thesis proposes that the early release of graft-derived Mt-DAMPs after LTx contributes to exacerbating ALI through an FPR1 dependent regulation of neutrophil intragraft trafficking and activation. Moreover, higher perioperative circulating levels of Mt- DNA in human LTx recipients appear to be a possible biomarker for the early detection of severe PGD.