The endogenous pro-resolving mediators lipoxin A4 and resolvin E1 preserve organ function in allograft rejection

Allograft rejection remains a major limitation to successful solid organ transplantation. Here, we investigated the biosynthesis and bioactions of the pro-resolving mediators lipoxin A4 and resolvin E1 in host responses to organ transplantation. In samples obtained during screening bronchoscopy after human lung transplantation, bronchoalveolar lavage fluid levels of lipoxin A4 were increased in association with the severity of allograft rejection that was graded independently by clinical pathology. Lipoxin A4 significantly inhibited calcineurin activation in human neutrophils, and lipoxin A4 stable analogs prevented acute rejection of vascularized cardiac and renal allografts. Transgenic animals expressing human lipoxin A4 receptors revealed important sites of action in host tissues for lipoxin A4’s protective effects. Resolvin E1 displays counter-regulatory actions for leukocytes, in part, via increased lipoxin A4 biosynthesis, yet RvE1 administered (1 μg, iv) to donor (days −1 and 0) and recipient mice (days −1, 0 and +4) was even more potent than a lipoxin stable analog (1 μg, iv) in prolonging renal allograft survival (median survival time=74.0 days with RvE1 and 37.5 days with a LXA4 analog). Together, these results highlight the potential for pro-resolving mediators in prolonging survival of solid organ transplants.