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

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