title: 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.
abstract: Lipoxins are endogenous lipoxygenase-derived eicosanoids, 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 aspirin-triggered 15-epi-lipoxin A(4) in ischemic acute renal failure (ARF) in NIH Swiss mice. ARF was induced by 30-min crossclamping of renal pedicles and was associated with elevated serum creatinine, morphologic injury, polymorphonuclear leukocyte (PMN) recruitment, and increased mRNA levels for adhesion molecules (intercellular adhesion molecule-1 [ICAM-1] and vascular cell adhesion molecule-1 [VCAM-1]), chemokines (growth regulated oncogene-1 [GRO1]), and cytokines (interleukin-1beta [IL-1beta] and IL-6) after 24-h reperfusion. 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. Treatment with 15-epi-16-(FPhO)-LXA(4)-Me was also associated with lower IL-1beta, IL-6, and GRO1 mRNA levels, whereas ICAM-1 and VCAM-1 mRNA levels were unchanged. Compatible with these results, LXA(4) blunted chemoattractant-stimulated PMN migration across HK-2 renal epithelial cell monolayers 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 signaling-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 protective 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.
authors.affiliation: Department of Medicine and Therapeutics, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland.
authors.forename: Martin O
authors.initials: MO
authors.lastname: Leonard
authors.forename: Kieran
authors.initials: K
authors.lastname: Hannan
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Burne
authors.forename: David W P
authors.initials: DW
authors.lastname: Lappin
authors.forename: Peter
authors.initials: P
authors.lastname: Doran
authors.forename: Patrick
authors.initials: P
authors.lastname: Coleman
authors.forename: Catherine
authors.initials: C
authors.lastname: Stenson
authors.forename: Cormac T
authors.initials: CT
authors.lastname: Taylor
authors.forename: Frank
authors.initials: F
authors.lastname: Daniels
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
authors.forename: Nicos A
authors.initials: NA
authors.lastname: Petasis
authors.forename: Hamid
authors.initials: H
authors.lastname: Rabb
authors.forename: Hugh R
authors.initials: HR
authors.lastname: Brady
mesh_terms: D058186:Acute Kidney Injury / Q000517:prevention & control*; D019883:Alkyl and Aryl Transferases / Q000235:genetics; D000818:Animals; D002352:Carrier Proteins / Q000235:genetics; D004268:DNA-Binding Proteins; D006893:Hydroxyeicosatetraenoic Acids / Q000627:therapeutic use*; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D007375:Interleukin-1 / Q000235:genetics; D015850:Interleukin-6 / Q000235:genetics; D007511:Ischemia / Q000188:drug therapy*; D007668:Kidney / Q000098:blood supply*; D044045:Lipoxins; D051379:Mice; D009504:Neutrophils / Q000187:drug effects / Q000502:physiology; D011506:Proteins / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D012097:Repressor Proteins; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1 / Q000235:genetics
chemical_list: C447621:16-(4-fluorophenoxy)lipoxin A4; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D006893:Hydroxyeicosatetraenoic Acids; D007375:Interleukin-1; D015850:Interleukin-6; D044045:Lipoxins; D011506:Proteins; D012333:RNA, Messenger; D012097:Repressor Proteins; C491590:Socs1 protein, mouse; C491409:Socs2 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D015534:Trans-Activators; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019883:Alkyl and Aryl Transferases; C023197:tRNA isopentenyltransferase