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

Abstract

SUMMARYAllograft 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 (1 µg, iv) to donor (days −1 and 0) and recipient mice (day −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 LXA 4 analog). Together, these results highlight the potential for pro-resolving mediators in prolonging survival of solid organ transplants.

Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease

“…Other SPMs (ResolvinE1, ProtectinD1 and D-series resolvins) attenuate obesity-induced liver disease (Claria et al, 2012; Gonzalez-Periz et al, 2009). LXA 4 enhances organ function in murine liver transplantation, attenuating serum ALT and inducing a pro-resolving shift in cytokine production, decreasing IFN-γ while increasing IL-10 (Levy et al, 2011; Liao et al, 2013). Recent data highlight a protective effect of LXs and other arachidonate-derived mediators in cardiovascular disease associated with increased reverse cholesterol transfer and lower plasma LDL (Demetz et al, 2014).…”

Report of the ISHLT Working Group on Primary Lung Graft Dysfunction Part III: Mechanisms: A 2016 Consensus Group Statement of the International Society for Heart and Lung Transplantation

“…77 One such molecule, lipoxin A4, has been detected in lung transplant recipient BAL and has known potent inhibitory effects on neutrophil transendothelial migration. 78 Another lipid mediator, reslovin E1, was demonstrated to promote human neutrophil apoptosis and clearance of neutrophils from inflamed lungs in mice. 79 Mesenchymal stem cells (MSCs), multipotent non-hematopoietic cells found in bone marrow and fatty tissues, have well-described immunosuppressive properties and have shown promise in ameliorating both acute and chronic pulmonary inflammation.…”

Obesity, immunomodulation and chronic kidney disease

“…Annexin-1 has also been shown to be protective in ischemia-reperfusion injury in the rat [56], although to our knowledge its effect as of yet has not been determined in CKD. Interestingly, LXs and RvE1 enhance survival following kidney transplantation in mice [57]. …”