BRIEF COMMUNICATION 15-Epi-16-(Para-Fluorophenoxy)-Lipoxin A 4 -Methyl Ester, a Synthetic Analogue of 15-epi-Lipoxin A 4 , Is Protective in Experimental Ischemic Acute Renal Failure MARTIN O. LEONARD,* KIERAN HANNAN,* MELISSA J. BURNE, † DAVID W. P. LAPPIN,* PETER DORAN,* PATRICK COLEMAN,* CATHERINE STENSON,* CORMAC T. TAYLOR,* FRANK DANIELS, † CATHERINE GODSON,* NICOS A. PETASIS, § HAMID RABB, † and HUGH R. BRADY* *Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Mater Misericordiae Hospital, and Dublin Molecular Medicine Centre, Dublin, Ireland; † Nephrology Division, Johns Hopkins University Hospital, Baltimore, Maryland; ‡ Nephrology Division, Hennepin County Medical Center, University of Minnesota, Minneapolis, Minnesota; and § Department of Chemistry, University of Southern California, Los Angeles, California. Abstract. Lipoxins are endogenous lipoxygenase-derived eico- sanoids, generated during inflammatory, hypersensitivity, and vascular events, that display vasodilatory, antiinflammatory, and pro-resolution activity. Here, we evaluated the efficacy of 15-epi-16-(para-fluorophenoxy)-lipoxin A 4 -methyl ester (15- epi-16-(FPhO)-LXA 4 -Me), a stable synthetic analogue of as- pirin-triggered 15-epi-lipoxin A 4 in ischemic acute renal fail- ure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with ele- vated serum creatinine, morphologic injury, polymorphonu- clear leukocyte (PMN) recruitment, and increased mRNA lev- els for adhesion molecules (intercellular adhesion molecule–1 [ICAM-1] and vascular cell adhesion molecule–1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cy- tokines (interleukin–1 [IL-1] and IL-6) after 24-h reperfu- sion. A single bolus of 15-epi-16-(FPhO)-LXA 4 -Me afforded striking functional (mean  SEM creatinine in mg/dl: sham- operated, 0.77  0.04; ARF + vehicle, 2.49  0.19; ARF + 15-epi-16-(FPhO)-LXA 4 -Me, 0.75  0.12; P  0.001) and morphologic protection and reduced PMN infiltration. Treat- ment with 15-epi-16-(FPhO)-LXA 4 -Me was also associated with lower IL-1, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Com- patible with these results, LXA 4 blunted chemoattractant-stim- ulated PMN migration across HK-2 renal epithelial cell mono- layers in vitro, but it did not inhibit cytokine-induced HK-2 ICAM-1 expression or adhesiveness for PMN. Interestingly 15-epi-16-(FPhO)-LXA 4 -Me–treated animals also displayed increased renal mRNA levels for suppressors of cytokine sig- naling–1 (SOCS-1) and SOCS-2, but not CIS-1, endogenous inhibitors of cytokine-elicited Jak/Stat-signaling pathways. These results indicate that 15-epi-16-(FPhO)-LXA 4 -Me is pro- tective in renal ischemia reperfusion injury in vivo, at least partially by modulating cytokine and chemokine expression and PMN recruitment, and provides a rationale for further exploration of the efficacy of LXA 4 structural analogues in ischemic ARF and other renal diseases. Ischemic acute renal failure (ARF) remains a formidable clin- ical problem for which there is no specific treatment (1). The pathophysiology of ARF is multifaceted and includes persis- tent intrarenal vasoconstriction, hypoxic tubule epithelial cell injury, and polymorphonuclear leukocyte (PMN)–mediated cy- totoxicity upon reperfusion (1,2). Despite the impressive effi- cacy of agents that specifically target these processes in exper- imental models, none has proved effective in randomized controlled clinical trials (1). These disappointing results have shifted attention toward regimens that simultaneously target two or more of the aforementioned pathophysiologic events. Lipoxins (LX) are lipoxygenase-derived arachidonate me- tabolites that are generated in a variety of human and experi- mental inflammatory, hypersensitivity, and vascular diseases (reviewed in references 3–5). They are generated principally by transcellular routes during cell-cell interactions by biosyn- thetic pathways initiated through the action of two lipoxygen- Dr. Martin O. Leonard and Dr. Kieran Hannan contributed equally to this work. Received October 30, 2001. Accepted February 15, 2002. Correspondence to Dr. Hugh R. Brady, Department of Medicine and Thera- peutics, University College Dublin, Mater Misericordiae Hospital, 41 Eccles Street, Dublin 7, Ireland. Phone: 353-1-803 2188; Fax: 353-1-830 8404; E-mail hrbrady@mater.ie 1046-6673/1306-1657 Journal of the American Society of Nephrology Copyright © 2002 by the American Society of Nephrology DOI: 10.1097/01.ASN.0000015795.74094.91 J Am Soc Nephrol 13: 1657–1662, 2002