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.